Compounds and compositions as inhibitors of mek

ABSTRACT

The present invention relates to compounds of formula I: 
     
       
         
         
             
             
         
       
         
         
           
             in which n, R 1 , R 2 , R 3a , R 4  and R 5  are defined in the Summary of the Invention; capable of inhibiting the activity of MEK. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of hyperproliferative diseases like cancer.

BACKGROUND

1. Field of the Invention

The present invention relates to compounds capable of selectivelyinhibiting the activity of MEK. The invention further provides a processfor the preparation of compounds of the invention, pharmaceuticalpreparations comprising such compounds and methods of using suchcompounds and compositions in the management of hyperproliferativediseases like cancer and inflammation.

2. Background of the Invention

Over activation of the mitogen-activated protein (MAP) kinase cascade isknown to play an important role in cell proliferation anddifferentiation. This pathway can be activated when a growth factorbinds to its receptor tyrosine kinase. This interaction promotes RASassociation with RAF and initiates a phosphorylation cascade through MEK(MAP kinase) to ERK. The only known substrates for MEK phosphorylationare the MAP kinases, ERK1 and ERK2. Phosphorylation of MEK increases itsaffinity and catalytic activity toward ERK as well as its affinity forATP. Constitutive activation of the MAPK pathway has been found in anumber of diseases, for example, melanoma, pancreatic, colon, lung,kidney and ovarian cancers; in particular pancreatic, colon, lung,kidney and ovarian cancers. Therefore, inhibition of this pathway,particularly inhibiting MEK activity, is known to be beneficial intreating hyperproliferative diseases.

Therefore, MEK represents a highly attractive target for the developmentof a novel therapy for the treatment of many forms of cancers. Inparticular, the need exists for small molecules that selectively inhibitthe activity of MEK. The present invention fulfills this need.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of formula I:

in which:

n is selected from 0, 1, 2 and 3;

R₁ is selected from:

R₂ is selected from chloro and methoxy;

R_(3a) is selected from cyano-methyl, 2-hydroxy-ethyl,1-hydroxypropan-2-yl, 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl,methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, dimethylcarbamoyl,3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl, 2-hydroxyacetyl,2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl,oxetan-2-yl, 2-aminoacetyl, oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl and carbamoyl;

R₄ is selected from hydrogen, halo, methyl and hydroxy-methyl; andoptionally two R₄ groups together with the carbon atoms to which theyare attached form —(CH₂)₂₋₃—; (for example,8-azabicyclo[3.2.1]octan-3-yl);

R₅ is selected from hydrogen and methyl;

R₆ is selected from hydrogen and halo;

R₇ is selected from hydrogen, fluoro, chloro, CH₂F, CHF₂, CF₃, CH₂OH,cyclopropyl and methyl; and

R₈ is selected from cyano.

In another aspect, the invention relates to a compound of the formula I

whereinn is selected from 0, 1, 2 and 3;R₁ is selected from:

R₂ is selected from chloro, methyl, hydrogen, fluoro and methoxy;R_(3a) is selected from cyano-methyl, 2-hydroxy-ethyl,1-hydroxypropan-2-yl, 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl,methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, dimethylcarbamoyl,3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl, 2-hydroxyacetyl,2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl,2-aminoacetyl, oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl, carbamoyl,(oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl,3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;each R₄ is independently selected from hydrogen, halo, methyl andhydroxy-methyl; and optionally two R₄ groups together with the carbonatoms to which they are attached form —(CH₂)₂₋₃—;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen, methoxy and halo;R₇ is selected from hydrogen, fluoro, CF₃, CH₂OH, cyclopropyl andmethyl; andR₈ is cyano;or the pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a pharmaceuticalcomposition which contains a compound of Formula I or a N-oxidederivative, tautomer, individual isomers and mixture of isomers thereof;or a pharmaceutically acceptable salt thereof, in admixture with one ormore suitable excipients.

In another aspect, the present invention provides a method of treating adisease in an animal in which modulation of MEK activity can prevent,inhibit or ameliorate the pathology and/or symptomology of the diseases,which method comprises administering to the animal a therapeuticallyeffective amount of a compound of Formula I or a N-oxide derivative,individual isomers and mixture of isomers thereof, or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention provides the use of a compoundof Formula I in the manufacture of a medicament for treating a diseasein an animal in which MEK activity contributes to the pathology and/orsymptomology of the disease.

In another aspect, the present invention provides a process forpreparing compounds of Formula I and the N-oxide derivatives, prodrugderivatives, protected derivatives, individual isomers and mixture ofisomers thereof, and the pharmaceutically acceptable salts thereof.

DEFINITIONS

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated, where more general terms whereever used may,independently of each other, be replaced by more specific definitions orremain, thus defining more detailed embodiments of the invention:

“Halogen” (or “halo”) preferably represents chloro or fluoro, inparticular fluoro, but may also be bromo or iodo. The term“dimethylcarbamoyl” as used herein refers to “N,N-dimethylcarbamoyl”(i.e. Me₂NC(═O)—).

Compounds of formula I may have different isomeric forms. For example,any asymmetric carbon atom may be present in the (R)-, (S)- or(R,S)-configuration, preferably in the (R)- or (S)-configuration.Substituents at a double bond or especially a ring may be present incis-(═Z—) or trans (=E—) form. The compounds may thus be present asmixtures of isomers or preferably as pure isomers, preferably as purediastereomers or pure enantiomers.

Compounds of formula I are selective MEK inhibitors. Selectivity of thecompounds for MEK is attributed to compounds of formula I contain afluoro atom linked directly to the 1H-imidazo[4,5-c]quinolone as shownin compounds A and B below. In the absence of a fluoro group at thisposition, the selectivity for MEK over other kinases is reduced. Forexample, comparing the following compounds:

Both compounds inhibit MEK at less than 100 nM and are equipotent.However, when tested against a kinase panel, the number of kinases inthe panel inhibited with an IC₅₀ of less than 100 nM is zero forcompound (A) and 4 for compound (B). That is, compound (A) is selectivefor MEK while compound (B) is less selective for MEK. Compound (B) alsoinhibits ABL1, LCK, LYN and PDGFRa at an IC₅₀ of 20 nM, 7 nM, 30 nM and50 nM, respectively.

A similar comparison shows that the following compounds selectivelyinhibit MEK and do not inhibit other kinases from the kinase panel withan IC₅₀ of less than 100 nM:

Compounds of the invention are screened, using assay conditions known inthe art, against some or all of the “Kinase Panel” comprising ABL1, ABL1(T315I), ACVR1, AKT1, ALK, AURKA, AXL, BTK, CAMK2D, CDK1B, CDK2A,CDK4D1, CSK, CSNK1G3, EGFR, EPHA4, EPHB4, ERBB4, FGFR1, FGFR2, FGFR3,FGFR3 (K650E), FGFR4, FLT3 (D835Y), IGF1R, GSK3B, INSR, IRAK4, JAK1,JAK2, JAK3, KDR, KIT, LCK, LYN, MAP3K8, MAPK1, MAPK10, MAPK14, MAPKAPK2,MAPKAPK5, MET, MKNK1, MKNK2, PAK2, PDGFRa, PDPK1, PIM2, PKN1, PKN2,PLK1, PRKACA, PRKCA, PRKCQ, RET, ROCK2, RPS6 KB1, SRC, SYK, TYK2, WNK1,ZAP70, PIKSCD, PIK3CG, MTOR, PIK3C3, PIK3CA, PIK3CB and PIK4CB.

The plural form (e.g. compounds, salts) is used, this includes thesingular (e.g. a single compound, a single salt). “A compound” does notexclude that (e.g. in a pharmaceutical formulation) more than onecompound of the formula I (or a salt thereof) is present, the “a” merelyrepresenting the indefinite article. “A” can thus preferably be read as“one or more”, less preferably alternatively as “one”.

Wherever a compound or compounds of the formula I are mentioned, this isfurther also intended to include N-oxides of such compounds and/ortautomers thereof.

The term “and/or an N-oxide thereof, a tautomer thereof and/or a(preferably pharmaceutically acceptable) salt thereof” especially meansthat a compound of the formula I may be present as such or in mixturewith its N-oxide, as tautomer (e.g. due to keto-enol, lactam-lactim,amide-imidic acid or enamine-imine tautomerism) or in (e.g. equivalencyreaction caused) mixture with its tautomer, or as a salt of the compoundof the formula I and/or any of these forms or mixtures of two or more ofsuch forms.

The present invention also includes all suitable isotopic variations ofthe compounds of the invention, or pharmaceutically acceptable saltsthereof. An isotopic variation of a compound of the invention or apharmaceutically acceptable salt thereof is defined as one in which atleast one atom is replaced by an atom having the same atomic number butan atomic mass different from the atomic mass usually found in nature.Examples of isotopes that may be incorporated into the compounds of theinvention and pharmaceutically acceptable salts thereof include, but arenot limited to, isotopes of hydrogen, carbon, nitrogen and oxygen suchas as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³⁵S, ¹⁸F, ³⁶Cl and ¹²³I.Certain isotopic variations of the compounds of the invention andpharmaceutically acceptable salts thereof, for example, those in which aradioactive isotope such as ³H or ¹⁴C is incorporated, are useful indrug and/or substrate tissue distribution studies. In particularexamples, ³H and ¹⁴C isotopes may be used for their ease of preparationand detectability. In other examples, substitution with isotopes such as²H may afford certain therapeutic advantages resulting from greatermetabolic stability, such as increased in vivo half-life or reduceddosage requirements. Isotopic variations of the compounds of theinvention or pharmaceutically acceptable salts thereof can generally beprepared by conventional procedures using appropriate isotopicvariations of suitable reagents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the XRPD pattern for Form A of the free form of1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention relates to compounds capable of inhibiting theactivity of MEK. In one embodiment, with respect to compounds of FormulaI, are compounds of Formula Ia:

in which: R₂ is selected from chloro and methoxy; R_(3a) is selectedfrom 2-hydroxy-ethyl, 1-hydroxypropan-2-yl, 2-methoxy-ethyl,(3-methyloxetan-3-yl)-methyl, methyl-sulfonyl, 2-acetoxyacetyl,2-fluoropropanoyl, 2-hydroxy-propyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, 3-hydroxy-2-(hydroxy-methyl)propyl,3-hydroxy-2-(hydroxy-methyl)propanoyl, oxetan-2-yl, dimethylcarbamoyl,(2,2,2-trifluoroethyl)carbamoyl, (S)-2-hydroxypropanoyl,oxetan-3-ylmethyl, 2-aminoacetyl, 2-methoxyacetyl, 2-hydroxyacetyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl and carbamoyl; R₄ isselected from hydrogen, methyl and hydroxy-methyl; R₅ is selected fromhydrogen and methyl; R₆ is selected from hydrogen and fluoro; R₇ isselected from hydrogen, fluoro, chloro, CH₂F, CHF₂, CF₃, CH₂OH,cyclopropyl and methyl; and R₈ is selected from cyano; or thepharmaceutically acceptable salts thereof.

In an further embodiment are compounds or pharmaceutically acceptablesalts thereof, selected from:

In another embodiment are compounds of formula Ib:

in which: n is selected from 0, 1 and 2; R₁ is selected from:

R₂ is selected from chloro and methoxy; R_(3a) is selected fromcyano-methyl, 2-hydroxy-ethyl, 1-hydroxypropan-2-yl, 2-methoxy-ethyl,(3-methyloxetan-3-yl)-methyl, methyl-sulfonyl, 2-fluoropropanoyl,2-hydroxy-propyl, cyclopropyl-sulfonyl, isopropyl-sulfonyl,3-hydroxy-2-(hydroxy-methyl)propyl, 2-acetoxyacetyl,3-hydroxy-2-(hydroxy-methyl)propanoyl, dimethylcarbamoyl,(2,2,2-trifluoroethyl)carbamoyl, (S)-2-hydroxypropanoyl, oxetan-2-yl,oxetan-3-ylmethyl, 2-aminoacetyl, 2-methoxyacetyl, 2-hydroxyacetyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl and carbamoyl; R₄ isselected from hydrogen, methyl and hydroxy-methyl; R₅ is selected fromhydrogen and methyl; and R₇ is selected from hydrogen, fluoro, chloro,CH₂F, CHF₂, CF₃, CH₂OH, cyclopropyl and methyl; or the pharmaceuticallyacceptable salts thereof.

In a further embodiment are compounds, or pharmaceutically acceptablesalts thereof, selected from:

In another embodiment are compounds of formula Ic:

in which: n is selected from 0, 1, 2 and 3; R₂ is selected from chloroand methoxy; R₄ is selected from fluoro; and optionally two R₄ groupstogether with the carbon atoms to which they are attached form—(CH₂)₂₋₃—; (for example, 8-azabicyclo[3.2.1]octan-3-yl); R₅ is selectedfrom hydrogen and methyl; R₆ is selected from hydrogen; and R₇ isselected from hydrogen, fluoro, chloro, CH₂F, CHF₂, CF₃, CH₂OH,cyclopropyl and methyl; or the pharmaceutically acceptable saltsthereof.

In a further embodiment are compounds, or pharmaceutically acceptablesalts thereof, selected from:

In another embodiment are compounds of formula Id:

in which: n is selected from 0, 1, 2 and 3; R₂ is selected from chloroand methoxy; R_(3a) is selected from 2-hydroxy-ethyl,1-hydroxypropan-2-yl, 2-methoxy-ethyl, (3-methyloxetan-3-yl)-methyl,methyl-sulfonyl, 2-hydroxy-propyl, 2-acetoxyacetyl, 2-fluoropropanoyl,cyclopropyl-sulfonyl, oxetan-2-yl, isopropyl-sulfonyl,3-hydroxy-2-(hydroxy-methyl)propyl,3-hydroxy-2-(hydroxy-methyl)propanoyl, dimethylcarbamoyl,(2,2,2-trifluoroethyl)carbamoyl, (S)-2-hydroxypropanoyl,oxetan-3-ylmethyl, 2-aminoacetyl, 2-methoxyacetyl, 2-hydroxyacetyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl and carbamoyl; R₄ isselected from fluoro; and optionally two R₄ groups together with thecarbon atoms to which they are attached form —(CH₂)₂₋₃—, R₅ is selectedfrom hydrogen and methyl; R₆ is selected from hydrogen and fluoro; andR₇ is selected from hydrogen, fluoro, chloro, CH₂F, CHF₂, CF₃, CH₂OH,cyclopropyl and methyl; or the pharmaceutically acceptable saltsthereof.

In a further embodiment are compounds, or pharmaceutically acceptablesalts thereof, selected from:

In another embodiment are compounds of formula Ie:

in which: R_(4a) and R_(4b) are derived from —(R₄)_(n); wherein n is 2;and R₄ of the Summary of the Invention is defined by R_(4a) and R_(4b);wherein R_(4a) is selected from hydrogen and methyl; and R_(4b) isselected from hydrogen and fluorine; R₁ is selected from:

R₂ is selected from chloro and methoxy; R_(3a) is selected from2-hydroxy-ethyl, 1-hydroxypropan-2-yl, 2-methoxy-ethyl,(3-methyloxetan-3-yl)-methyl, methyl-sulfonyl, 2-hydroxy-propyl,2-acetoxyacetyl, 2-fluoropropanoyl, cyclopropyl-sulfonyl, oxetan-2-yl,isopropyl-sulfonyl, 3-hydroxy-2-(hydroxy-methyl)propyl,3-hydroxy-2-(hydroxy-methyl)propanoyl, dimethylcarbamoyl,(2,2,2-trifluoroethyl)carbamoyl, (S)-2-hydroxypropanoyl,oxetan-3-ylmethyl, 2-aminoacetyl, 2-methoxyacetyl, 2-hydroxyacetyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl and carbamoyl; R₅ isselected from hydrogen and methyl; R₆ is selected from hydrogen andfluoro; R₇ is selected from hydrogen, fluoro, chloro, CH₂F, CHF₂, CF₃,CH₂OH, cyclopropyl and methyl; and R₈ is selected from cyano; or thepharmaceutically acceptable salts thereof.

In a further embodiment are compounds, or a pharmaceutically acceptablesalt thereof, selected from:

Further Embodiments of the Invention Embodiment 1

A compound of formula I:

whereinn is selected from 0, 1, 2 and 3;R₁ is selected from:

R₂ is selected from chloro, methyl, hydrogen, fluoro and methoxy;R_(3a) is selected from cyano-methyl, 2-hydroxy-ethyl,1-hydroxypropan-2-yl, 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl,methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, dimethylcarbamoyl,3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl, 2-hydroxyacetyl,2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl,2-aminoacetyl, oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl, carbamoyl,(oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl,3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;each R₄ is independently selected from hydrogen, halo, methyl andhydroxy-methyl; and optionally two R₄ groups together with the carbonatoms to which they are attached form —(CH₂)₂₋₃—;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen, methoxy and halo;R₇ is selected from hydrogen, fluoro, CF₃, CH₂OH, cyclopropyl andmethyl; andR₈ is selected from cyano;or the pharmaceutically acceptable salts thereof.

Embodiment 2

The compound of formula I, according to embodiment 1,

whereinn is selected from 0 or 1;R₁ is selected from:

R₂ is selected from chloro, methyl, hydrogen, fluoro and methoxy;R_(3a) is selected from cyano-methyl, 2-hydroxy-ethyl,1-hydroxypropan-2-yl, 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl,methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, dimethylcarbamoyl,3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl, 2-hydroxyacetyl,2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl,2-aminoacetyl, oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl, carbamoyl,(oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl,3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;each R₄ is independently selected from halo, methyl and hydroxy-methyl;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen, methoxy and halo;R₇ is selected from hydrogen, fluoro, CF₃, CH₂OH, cyclopropyl andmethyl; andR₈ is selected from cyano;or the pharmaceutically acceptable salts thereof.

Embodiment 3

The compound of formula I, according to embodiment 1,

whereinn is selected from 0 or 1;R₁ is selected from:

R₂ is selected from chloro, methyl, hydrogen, fluoro and methoxy;R_(3a) is selected from cyano-methyl, 2-hydroxy-ethyl,1-hydroxypropan-2-yl, 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl,methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, dimethylcarbamoyl,3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl, 2-hydroxyacetyl,2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl,2-aminoacetyl, oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl, carbamoyl,(oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl,3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;each R₄ is independently selected from halo, methyl and hydroxy-methyl;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen and halo; andR₇ is selected from hydrogen, fluoro, CF₃, CH₂OH, cyclopropyl andmethyl;or the pharmaceutically acceptable salts thereof.

Embodiment 4

The compound of formula I, according to embodiment 1,

whereinn is selected from 0 or 1;R₁ is selected from:

R₂ is selected from chloro, methyl, hydrogen, fluoro and methoxy;R_(3a) is selected from cyano-methyl,3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-methoxy-ethyl,2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl, methyl-sulfonyl,amino-carbonyl-methyl, cyclopropyl-sulfonyl, isopropyl-sulfonyl,dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl,(2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, oxetan-3-ylmethyl,(S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl,carbamoyl, (oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl,2-fluoroethanoyl, 3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;each R₄ is independently from halo, methyl and hydroxy-methyl;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen and halo; andR₇ is selected from hydrogen, fluoro, CF₃, CH₂OH, cyclopropyl andmethyl;or the pharmaceutically acceptable salts thereof.

Embodiment 5

The compound of formula I, according to embodiment 1,

whereinn is selected from 0 or 1;R₁ is selected from:

R₂ is selected from chloro, methyl, hydrogen, fluoro and methoxy;R_(3a) is selected from 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl, methyl-sulfonyl,amino-carbonyl-methyl, cyclopropyl-sulfonyl, isopropyl-sulfonyl,dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl,(2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, oxetan-3-ylmethyl,(S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl,carbamoyl, (oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl,2-fluoroethanoyl, 3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;each R₄ is independently selected from halo, methyl and hydroxy-methyl;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen and halo; andR₇ is selected from hydrogen, fluoro, CF₃, CH₂OH, cyclopropyl andmethyl;or the pharmaceutically acceptable salts thereof.

Embodiment 6

The compound of formula I, according to embodiment 1,

whereinn is selected from 0 or 1;R₁ is selected from:

R₂ is selected from chloro, methyl, hydrogen, fluoro and methoxy;R_(3a) is selected from 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-fluoropropanoyl, methyl-sulfonyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl,2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl,(S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, carbamoyl,2-(sulfooxy)acetyl, 2-fluoroethanoyl, 3-hydroxypropanoyl, andN,N-dimethylsulfonamidyl;each R₄ is independently selected from halo, methyl and hydroxy-methyl;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen and halo; andR₇ is selected from hydrogen, fluoro, CF₃, CH₂OH, cyclopropyl andmethyl;or the pharmaceutically acceptable salts thereof.

Embodiment 7

The compound of formula I, according to embodiment 1,

whereinn is selected from 0 or 1;R₁ is selected from:

R₂ is selected from chloro, methyl, hydrogen, fluoro and methoxy;R_(3a) is selected from 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-fluoropropanoyl, dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl,2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl,(S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, carbamoyl,2-(sulfooxy)acetyl, 2-fluoroethanoyl and 3-hydroxypropanoyl;each R₄ is independently selected from halo, methyl and hydroxy-methyl;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen and halo; andR₇ is selected from hydrogen, fluoro, CF₃, CH₂OH, cyclopropyl andmethyl;or the pharmaceutically acceptable salts thereof.

Embodiment 8

The compound of formula I, according to embodiment 1,

whereinn is selected from 0 or 1;R₁ is selected from:

R₂ is selected from chloro and methoxy;R_(3a) is selected from 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-fluoropropanoyl, dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl,2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl,(S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, carbamoyl,2-(sulfooxy)acetyl, 2-fluoroethanoyl and 3-hydroxypropanoyl;each R₄ is independently selected from halo, methyl and hydroxy-methyl;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen and halo; andR₇ is selected from hydrogen, fluoro, CF₃, CH₂OH, cyclopropyl andmethyl;or the pharmaceutically acceptable salts thereof.

Embodiment 9

The compound of formula I, according to embodiment 1,

whereinn is selected from 0 or 1;R₁ is selected from:

R₂ is selected from chloro and methoxy;R_(3a) is selected from 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-fluoropropanoyl, dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl,2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl,(S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, carbamoyl,2-(sulfooxy)acetyl, 2-fluoroethanoyl and 3-hydroxypropanoyl;each R₄ is independently selected from halo, methyl and hydroxy-methyl;R₅ is selected from hydrogen and methyl;R₆ is hydrogen; andR₇ is hydrogen;or the pharmaceutically acceptable salts thereof.

Embodiment 10

The compound of formula I, according to embodiment 1,

whereinn is selected from 0 or 1;R₁ is selected from:

R₂ is selected from chloro and methoxy;R_(3a) is selected from 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-fluoropropanoyl, dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl,2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl,(S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, carbamoyl,2-(sulfooxy)acetyl, 2-fluoroethanoyl and 3-hydroxypropanoyl;each R₄ is independently selected from halo, methyl and hydroxy-methyl;R₅ is methyl;R₆ is hydrogen; andR₇ is hydrogen;or the pharmaceutically acceptable salts thereof.

Embodiment 11

The compound of formula I, according to embodiment 1,

whereinn is selected from 0 or 1;R₁ is selected from:

R₂ is chloro;R_(3a) is selected from 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-fluoropropanoyl, dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl,2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl,(S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, carbamoyl,2-(sulfooxy)acetyl, 2-fluoroethanoyl and 3-hydroxypropanoyl;each R₄ is independently selected from halo, methyl and hydroxy-methyl;R₅ is methyl;R₆ is hydrogen; andR₇ is hydrogen;or the pharmaceutically acceptable salts thereof.

Embodiment 12

The compound of formula I, according to embodiment 1,

whereinn is selected from 0 or 1;R₁ is selected from:

R₂ is chloro;R_(3a) is selected from 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-fluoropropanoyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl,2-aminoacetyl, (S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl,2-(sulfooxy)acetyl, 2-fluoroethanoyl and 3-hydroxypropanoyl;each R₄ is independently selected from halo, methyl and hydroxy-methyl;R₅ is methyl;R₆ is hydrogen; andR₇ is hydrogen;or the pharmaceutically acceptable salts thereof.

Embodiment 13

A compound of formula Ie:

whereinR₁ is selected from:

R₂ is selected from chloro, methyl, fluoro and methoxy;R_(3a) is selected from cyano-methyl, 2-hydroxy-ethyl,1-hydroxypropan-2-yl, 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl,methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, dimethylcarbamoyl,3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl, 2-hydroxyacetyl,2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl,2-aminoacetyl, oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl, carbamoyl,(oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl,3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;R_(4a) is hydrogen;R_(4b) is selected from hydrogen and fluorine;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen and fluoro;R₇ is selected from hydrogen, fluoro, CF₃, CH₂OH, cyclopropyl andmethyl; andR₈ is cyano;or the pharmaceutically acceptable salts thereof.

Embodiment 14

The compound of formula Ie, according to embodiment 13,

whereinR₁ is selected from:

R₂ is selected from chloro, methyl, fluoro and methoxy;R_(3a) is selected from cyano-methyl, 2-hydroxy-ethyl,1-hydroxypropan-2-yl, 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl,methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, dimethylcarbamoyl,3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl, 2-hydroxyacetyl,2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl,2-aminoacetyl, oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl, carbamoyl,(oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl,3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;R_(4a) is hydrogen;R_(4b) is fluorine;R₅ is methyl;R₆ is selected from hydrogen and fluoro;R₇ is selected from hydrogen, fluoro, CF₃, CH₂OH, cyclopropyl andmethyl; andR₈ is cyano;or the pharmaceutically acceptable salts thereof.

Embodiment 15

The compound of formula Ie, according to embodiment 13,

whereinR₁ is selected from:

R₂ is selected from chloro, methyl, fluoro and methoxy;R_(3a) is selected from cyano-methyl, 2-hydroxy-ethyl,1-hydroxypropan-2-yl, 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl,methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, dimethylcarbamoyl,3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl, 2-hydroxyacetyl,2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl,2-aminoacetyl, oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl, carbamoyl,(oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyl,3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;R_(4a) is hydrogen;R_(4b) is fluorine;R₅ is methyl;R₆ is selected from hydrogen and fluoro; andR₇ is selected from hydrogen, CF₃, CH₂OH, and methyl;or the pharmaceutically acceptable salts thereof.

Embodiment 16

The compound of formula Ie, according to embodiment 13,

whereinR₁ is selected from:

R₂ is selected from chloro, methyl, fluoro and methoxy;R_(3a) is selected from cyano-methyl,3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-methoxy-ethyl,2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl, methyl-sulfonyl,amino-carbonyl-methyl, cyclopropyl-sulfonyl, isopropyl-sulfonyl,dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl,(2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, oxetan-3-ylmethyl,(S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl,carbamoyl, (oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl,2-fluoroethanoyl, 3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;R_(4a) is hydrogen;R_(4b) is fluorine;R₅ is methyl;R₆ is selected from hydrogen and fluoro; andR₇ is selected from hydrogen, CF₃, CH₂OH, and methyl;or the pharmaceutically acceptable salts thereof.

Embodiment 17

The compound of formula Ie, according to embodiment 13,

whereinR₁ is selected from:

R₂ is selected from chloro, methyl, fluoro and methoxy;R_(3a) is selected from cyano-methyl,3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-fluoropropanoyl,methyl-sulfonyl, cyclopropyl-sulfonyl, isopropyl-sulfonyl,dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl,(2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, (S)-2-hydroxypropanoyl,2-hydroxypropanoyl, acetyl, carbamoyl, (oxetan-2-yl)-methanoyl,2-(sulfooxy)acetyl, 2-fluoroethanoyl, 3-hydroxypropanoyl, andN,N-dimethylsulfonamidyl;R_(4a) is hydrogen;R_(4b) is fluorine;R₅ is methyl;R₆ is selected from hydrogen and fluoro; andR₇ is selected from hydrogen, CF₃, CH₂OH, and methyl;or the pharmaceutically acceptable salts thereof.

Embodiment 18

The compound of formula Ie, according to embodiment 13,

whereinR₁ is selected from:

R₂ is selected from chloro, methyl, fluoro and methoxy;R_(3a) is selected from cyano-methyl, methyl-sulfonyl, 2-hydroxyacetyl,2-acetoxyacetyl, 2-methoxyacetyl, (S)-2-hydroxypropanoyl, acetyl,carbamoyl, (oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyland 3-hydroxypropanoyl;R_(4a) is hydrogen;R_(4b) is fluorine;R₅ is methyl;R₆ is selected from hydrogen and fluoro; andR₇ is selected from hydrogen, CF₃, CH₂OH, and methyl;or the pharmaceutically acceptable salts thereof.

Embodiment 19

A pharmaceutical composition comprising a compound according to any oneof embodiments 1 to 18, or a pharmaceutically acceptable salt thereof,and at least one pharmaceutically acceptable carrier.

Embodiment 20

A combination comprising a compound according to any one of embodiments1 to 18, or a pharmaceutically acceptable salt thereof, and one or moretherapeutically active agents, for example selected from:

-   i) PI3K inhibitors, such as BKM120 [i.e.    5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine]    or BYL719 [i.e.    (S)—N-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide];-   ii) compounds targeting, decreasing or inhibiting the activity of    members of the protein kinase C (PKC) and Raf family of    serine/threonine kinases, members of the MEK, ERK, SRC, JAK, FAK,    PDK1, PKB/Akt, and Ras/MAPK family members, and/or members of the    cyclin-dependent kinase family (CDK); such as Dabrafenib,    Encorafenib ot LEE011 (i.e.,    7-cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide);    and-   iii) mTOR inhibitors, such as Everolimus.

Embodiment 20a

A combination comprising a compound according to any one of embodiments1 to 18, or a pharmaceutically acceptable salt thereof, and one or moretherapeutically active agents, such as PI3K inhibitors, such as BKM120[i.e.5-(2,6-dimoipholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine]or BYL719 [i.e.(S)—N-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide].

Embodiment 20b

A combination comprising a compound according to any one of embodiments1 to 18, or a pharmaceutically acceptable salt thereof, and one or moretherapeutically active agents, such as compounds targeting, decreasingor inhibiting the activity of members of the protein kinase C(PKC) andRaf family of serine/threonine kinases, members of the MEK, ERK, SRC,JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK family members, and/or members ofthe cyclin-dependent kinase family (CDK); such as Dabrafenib,Encorafenib ot LEE011 (i.e.,7-cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide).

Embodiment 20c

A combination comprising a compound according to any one of embodiments1 to 18, or a pharmaceutically acceptable salt thereof, and one or moretherapeutically active agents, such as mTOR inhibitors, such asEverolimus.

Embodiment 21

A compound according to any one of embodiments 1 to 18, or apharmaceutically acceptable salt thereof, for use as a medicament.

Embodiment 22

A compound according to any one of embodiments 1 to 18, or apharmaceutically acceptable salt thereof, for use in the treatment of adisorder or disease which is mediated by the activity of MEK, forexample a disease or disorder selected from ovarian carcinoma, kidneycancer, prostate cancer, breast carcinoma, lymphomas, myeloma, bladdercarcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma,endometrial cancer, lung cancer, pancreatic cancer, gastric cancer andsoft tissue sarcomas selected from rhabdomyosarcoma, synovial sarcomaand Ewing sarcoma; in particular melanoma, pancreatic, colon, lung,kidney and ovarian cancers.

Embodiment 23

Use of a compound according to any one of embodiments 1 to 18, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of a disorder or disease which is mediatedby the activity of MEK, for example a disease or disorder selected fromovarian carcinoma, kidney cancer, prostate cancer, breast carcinoma,lymphomas, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma,hepatocellular carcinoma, endometrial cancer, lung cancer, pancreaticcancer, gastric cancer and soft tissue sarcomas selected fromrhabdomyosarcoma, synovial sarcoma and Ewing sarcoma; in particularmelanoma, pancreatic, colon, lung, kidney and ovarian cancers.

Embodiment 24

A pharmaceutical composition according to embodiment 19 for use in thetreatment of a disorder or disease which is mediated by the activity ofMEK, for example a disease or disorder selected from ovarian carcinoma,kidney cancer, prostate cancer, breast carcinoma, lymphomas, myeloma,bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellularcarcinoma, endometrial cancer, lung cancer, pancreatic cancer, gastriccancer and soft tissue sarcomas selected from rhabdomyosarcoma, synovialsarcoma and Ewing sarcoma; in particular melanoma, pancreatic, colon,lung, kidney and ovarian cancers.

Embodiment 25

A method of treatment an MEK-mediated disorder comprising the step ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to any one of embodiments 1 to 18, or apharmaceutically acceptable salt thereof.

Embodiment 26

The method of embodiment 25 wherein said MEK-mediated disorders areselected from ovarian carcinoma, kidney cancer, prostate cancer, breastcarcinoma, lymphomas, myeloma, bladder carcinoma, colon cancer,cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, lungcancer, pancreatic cancer, gastric cancer and soft tissue sarcomasselected from rhabdomyosarcoma, synovial sarcoma and Ewing sarcoma; inparticular melanoma, pancreatic, colon, lung, kidney and ovariancancers.

Further Embodiments

Preferred substituents present in compounds of the formula I, or offormula (Ie), are defined below. The definition of the substituentsapplies to the end-products as well as to the correspondingintermediates. In addition, the definitions of the substituent, asprovided below, may be combined at will, e.g. preferred substituentsR_(3a) and preferred substituents R₄.

In one embodiment, the compound of the invention is a compound offormula (I), as defined herein, wherein n is 0.

In one embodiment, the compound of the invention is a compound offormula (I), as defined herein, wherein n is 1.

In one embodiment, the compound of the invention is a compound offormula (I), as defined herein, wherein R₁ is

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₁ is

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₁ is

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₁ is

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₁ is

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₁ is

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₁ is

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₁ is

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₂ ischloro.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₂ ismethyl.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₂ ishydrogen.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₂ isfluoro.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₂ ismethoxy.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R_(3a) isselected from cyano-methyl, 2-hydroxy-ethyl, 1-hydroxypropan-2-yl,2-methoxy-ethyl, (3-methyloxetan-3-yl)-methyl, amino-carbonyl-methyl,3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl, oxetan-3-ylmethyland 2-amino-2-oxoethyl; in particular cyano-methyl, 2-methoxy-ethyl,(3-methyloxetan-3-yl)-methyl, amino-carbonyl-methyl, oxetan-3-ylmethyland 2-amino-2-oxoethyl; such as cyano-methyl.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R_(3a) isselected from 3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-fluoropropanoyl,dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl,(2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, (S)-2-hydroxypropanoyl,2-hydroxypropanoyl, acetyl, carbamoyl, (oxetan-2-yl)-methanoyl,2-(sulfooxy)acetyl, 2-fluoroethanoyl and 3-hydroxypropanoyl; inparticular 3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-hydroxyacetyl,(S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, and 3-hydroxypropanoyl; suchas 2-hydroxyacetyl.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R_(3a) isselected from methyl-sulfonyl, cyclopropyl-sulfonyl, isopropyl-sulfonyland N,N-dimethylsulfonamidyl.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R_(3a) isselected from methyl-sulfonyl, cyclopropyl-sulfonyl, isopropyl-sulfonyland N,N-dimethylsulfonamidyl.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R_(3a) isselected from dimethylcarbamoyl, (2,2,2-trifluoroethyl)carbamoyl andcarbamoyl.

In one embodiment, the compound of the invention is a compound offormula (I), as defined herein, wherein R₄ is hydrogen.

In one embodiment, the compound of the invention is a compound offormula (I), as defined herein, wherein R₄ is halo, in particularfluoro.

In one embodiment, the compound of the invention is a compound offormula (I), as defined herein, wherein R₄ is methyl or hydroxy-methyl.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₅ ishydrogen.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₅ ismethyl.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₆ ishydrogen.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₆ ismethoxy.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₆ is halo,in particular fluoro.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₇ isselected from fluoro, cyclopropyl, CF₃ and CH₂OH.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₇ ishydrogen.

In one embodiment, the compound of the invention is a compound offormula (I), or of formula (Ie), as defined herein, wherein R₇ ismethyl.

In one embodiment, the compound of the invention is a compound offormula (Ie), as defined herein, wherein R_(4a) is hydrogen.

In one embodiment, the compound of the invention is a compound offormula (Ie), as defined herein, wherein R_(4a) is methyl.

In one embodiment, the compound of the invention is a compound offormula (Ie), as defined herein, wherein R_(4b) is fluorine.

Yet Further Embodiments Embodiment 1″

A compound of formula I:

n is selected from 0, 1, 2 and 3;R₁ is selected from:

R₂ is selected from chloro and methoxy;R_(3a) is selected from cyano-methyl, 2-hydroxy-ethyl,1-hydroxypropan-2-yl, 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl,methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, dimethylcarbamoyl,3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl, 2-hydroxyacetyl,2-acetoxyacetyl, 2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl,oxetan-2-yl, 2-aminoacetyl, oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl and carbamoyl;R₄ is selected from hydrogen, halo, methyl and hydroxy-methyl; andoptionally two R₄ groups together with the carbon atoms to which theyare attached form —(CH₂)₂₋₃—;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen and halo;R₇ is selected from hydrogen, fluoro, chloro, CH₂F, CHF₂, CF₃, CH₂OH,cyclopropyl and methyl; andR₈ is selected from cyano; or the pharmaceutically acceptable saltsthereof.

Embodiment 2″

The compound of embodiment 1″ of formula Ia:

in which:R₂ is selected from chloro and methoxy;R_(3a) is selected from 2-hydroxy-ethyl, 1-hydroxypropan-2-yl,2-methoxy-ethyl, (3-methyloxetan-3-yl)-methyl, methyl-sulfonyl,2-acetoxyacetyl, 2-fluoropropanoyl, 2-hydroxy-propyl,cyclopropyl-sulfonyl, isopropyl-sulfonyl,3-hydroxy-2-(hydroxy-methyl)propyl,3-hydroxy-2-(hydroxy-methyl)propanoyl, oxetan-2-yl, dimethylcarbamoyl,(2,2,2-trifluoroethyl)carbamoyl, (S)-2-hydroxypropanoyl,oxetan-3-ylmethyl, 2-aminoacetyl, 2-methoxyacetyl, 2-hydroxyacetyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl and carbamoyl;R₄ is selected from hydrogen, methyl and hydroxy-methyl;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen and fluoro;R₇ is selected from hydrogen, fluoro, chloro, CH₂F, CHF₂, CF₃, CH₂OH,cyclopropyl and methyl; andR₈ is selected from cyano; or the pharmaceutically acceptable saltsthereof.

Embodiment 3″

The compound of embodiment 2″ selected from:

Embodiment 4″

The compound of embodiment 1″ of formula Ib:

in which:n is selected from 0, 1 and 2;R₁ is selected from:

R₂ is selected from chloro and methoxy;R_(3a) is selected from cyano-methyl, 2-hydroxy-ethyl,1-hydroxypropan-2-yl, 2-methoxy-ethyl, (3-methyloxetan-3-yl)-methyl,methyl-sulfonyl, 2-fluoropropanoyl, 2-hydroxy-propyl,cyclopropyl-sulfonyl, isopropyl-sulfonyl,3-hydroxy-2-(hydroxy-methyl)propyl, 2-acetoxyacetyl,3-hydroxy-2-(hydroxy-methyl)propanoyl, dimethylcarbamoyl,(2,2,2-trifluoroethyl)carbamoyl, (S)-2-hydroxypropanoyl, oxetan-2-yl,oxetan-3-ylmethyl, 2-aminoacetyl, 2-methoxyacetyl, 2-hydroxyacetyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl and carbamoyl;R₄ is selected from hydrogen, methyl and hydroxy-methyl;R₅ is selected from hydrogen and methyl;R₇ is selected from hydrogen, fluoro, chloro, CH₂F, CHF₂, CF₃, CH₂OH,cyclopropyl and methyl; andR₈ is selected from cyano; or the pharmaceutically acceptable saltsthereof.

Embodiment 5″

The compound of embodiment 4″ selected from:

Embodiment 6″

The compound of embodiment 1″ of formula Ic:

in which:n is selected from 0, 1, 2 and 3;R₂ is selected from chloro and methoxy;R₄ is selected from fluoro; and optionally two R₄ groups together withthe carbon atoms to which they are attached form —(CH₂)₂₋₃—;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen and fluoro; andR₇ is selected from hydrogen, fluoro, chloro, CH₂F, CHF₂, CF₃, CH₂OH,cyclopropyl and methyl; or the pharmaceutically acceptable saltsthereof.

Embodiment 7″

The compound of embodiment 6″, or the pharmaceutically acceptable saltsthereof, selected from:

Embodiment 8″

The compound of embodiment 1″ of formula Id:

in which:n is selected from 0, 1, 2 and 3;R₂ is selected from chloro and methoxy;R_(3a) is selected from 2-hydroxy-ethyl, 1-hydroxypropan-2-yl,2-methoxy-ethyl, (3-methyloxetan-3-yl)-methyl, methyl-sulfonyl,2-hydroxy-propyl, 2-acetoxyacetyl, 2-fluoropropanoyl,cyclopropyl-sulfonyl, oxetan-2-yl, isopropyl-sulfonyl,3-hydroxy-2-(hydroxy-methyl)propyl,3-hydroxy-2-(hydroxy-methyl)propanoyl, dimethylcarbamoyl,(2,2,2-trifluoroethyl)carbamoyl, (S)-2-hydroxypropanoyl,oxetan-3-ylmethyl, 2-aminoacetyl, 2-methoxyacetyl, 2-hydroxyacetyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl and carbamoyl;R₄ is selected from fluoro; and optionally two R₄ groups together withthe carbon atoms to which they are attached form —(CH₂)₂₋₃—;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen and fluoro; andR₇ is selected from hydrogen, fluoro, chloro, CH₂F, CHF₂, CF₃, CH₂OH,cyclopropyl and methyl; or the pharmaceutically acceptable saltsthereof.

Embodiment 9″

The compound of embodiment 8″, or the pharmaceutically acceptable saltsthereof, selected from:

Embodiment 10″

The compound of embodiment 1″ of formula Ie:

in which:R₁ is selected from:

R₂ is selected from chloro and methoxy;R_(3a) is selected from 2-hydroxy-ethyl, 1-hydroxypropan-2-yl,2-methoxy-ethyl, (3-methyloxetan-3-yl)-methyl, methyl-sulfonyl,2-hydroxy-propyl, 2-acetoxyacetyl, 2-fluoropropanoyl,cyclopropyl-sulfonyl, oxetan-2-yl, isopropyl-sulfonyl,3-hydroxy-2-(hydroxy-methyl)propyl,3-hydroxy-2-(hydroxy-methyl)propanoyl, dimethylcarbamoyl,(2,2,2-trifluoroethyl)carbamoyl, (S)-2-hydroxypropanoyl,oxetan-3-ylmethyl, 2-aminoacetyl, 2-methoxyacetyl, 2-hydroxyacetyl,2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl and carbamoyl;R_(4a) is selected from hydrogen and methyl;R_(4b) is selected from hydrogen and fluorine;R₅ is selected from hydrogen and methyl;R₆ is selected from hydrogen and fluoro;R₇ is selected from hydrogen, fluoro, chloro, CH₂F, CHF₂, CF₃, CH₂OH,cyclopropyl and methyl; andR₈ is selected from cyano; or the pharmaceutically acceptable saltsthereof.

Embodiment 11″

The compound of embodiment 10″, or a pharmaceutically acceptable saltthereof, selected from:

Embodiment 12″

A pharmaceutical composition comprising a compound of embodiment 1″ or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.

Embodiment 13″

A pharmaceutical composition according to embodiment 12″ for use in thetreatment of a disorder or disease which is mediated by the activity ofMEK.

Embodiment 14″

A method of treatment an MEK-mediated disorder comprising the step ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound of embodiment 1″, or a pharmaceutically acceptablesalt thereof.

Embodiment 15″

The method of embodiment 14″ wherein said MEK-mediated disorders areselected from prostate cancer, breast carcinoma, lymphomas, myeloma,bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellularcarcinoma, endometrial cancer, lung cancer, pancreatic cancer, gastriccancer and soft tissue sarcomas selected from rhabdomyosarcoma, synovialsarcoma and Ewing sarcoma.

Pharmacology and Utility

Hyperproliferative diseases like cancer and inflammation are receiving alot of attention from the scientific community and there is a strongdesire to discover compounds that provide therapeutic benefits withregard to treating hyperproliferative diseases. In this regard effortshave been made to identify and target specific mechanisms which play arole in these diseases.

One target of interest is the over-activation of mitogen-activatedprotein (MAP) kinase cascade which is known to play an important role incell proliferation and differentiation. This pathway can be activatedwhen a growth factor binds to its receptor tyrosine kinase. Thisinteraction promotes RAS association with RAF and initiates aphosphorylation cascade through MEK (MAP kinase) to ERK. Inhibition ofthis pathway is known to be beneficial in treating hyperproliferativediseases. MEK is an attractive therapeutic target because the only knownsubstrates for MEK phosphorylation are the MAP kinases, ERK1 and ERK2.Constitutive activation of MEK/ERK has been found in pancreatic, colon,lung, kidney and ovarian primary tumor samples.

Phosphorylation of MEK increases its affinity and its catalytic activitytoward ERK as well as its affinity for ATP. This invention describescompounds that inhibit MEK activity by modulating ATP binding and theassociation of MEK with ERK by a mechanism that is ATP-competitive.

Activation of MEK has been demonstrated in many disease modelssuggesting that inhibition of MEK could have potential therapeuticbenefit in various diseases such as Pain (see, e.g., Evidence ofefficacy in pain models described in J. Neurosci. 22:478, 2002; ActaPharmacol Sin. 26:789 2005; Expert Opin Ther Targets. 9:699, 2005; andMol. Pain. 2:2, 2006): Stroke (see, e.g., Evidence of efficacy in strokemodels significant neuroprotection against ischemic brain injury byinhibition of the MEK described in J. Pharmacol. Exp. Ther. 304:172,2003; and Brain Res. 996:55, 2004); Diabetes (see, e.g., Evidence indiabetic complications described in Am. J. Physiol. Rena1.286, F1202004); Inflammation (see e.g., Evidence of efficacy in inflammationmodels described in Biochem Biophy. Res. Com. 268:647, 2000); andArthritis (see, e.g, Evidence of efficacy in experimental osteoarthritisand arthritis as described in J. Clin. Invest. 116:163. 2006).

The present invention relates to compounds capable of inhibiting theactivity of MEK. The invention further provides a process for thepreparation of compounds of the invention and pharmaceuticalpreparations comprising such compounds. Another aspect of the presentinvention relates to a method of treating MEK-mediated disorderscomprising the step of administering to a patient in need thereof atherapeutically effective amount of a compound of formula I as definedin the Summary of the Invention.

In certain embodiments, the present invention relates to theaforementioned method, wherein said MEK-mediated disorders are cancersselected from, but not limited to: angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma,teratoma; bronchogenic carcinoma, squamous cell carcinoma,undifferentiated small cell carcinoma, undifferentiated large cellcarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma,lymphoma, chondromatous hanlartoma, inesothelioma, esophageal squamouscell carcinoma, leiomyosarcoma, leiomyosarcoma, ductal adenocarcinoma,insulinorna, glucagonoma, gastrinoma, vipoma, stomach and small bowelcarcinoid tumors, adenocarcinoma, Karposi's sarcoma, leiomyoma,hemangioma, lipoma, neurofibroma, fibroma, tubular adenoma, villousadenoma, hamartoma, Wilm's tumor [nephroblastoma, leukemia, bladder andurethra squamous cell carcinoma, transitional cell carcinoma,adenocarcinoma, seminoma, teratoma, embryonal carcinoma,teratocareinoma, choriocarcinoma, interstitial cell carcinoma,fibroadenoma, adenomatoid tumors, hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, hemangioma,osteogenic sarcoma (osteosarcoma), malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lyinphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors, osteoma, granuloma, xanthoma, osteitis deformians, meningioma,meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma,ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinalcord neurofibroma, meningioma, glioma, endometrial carcinoma, cervicalcarcinoma, pre-tumor cervical dysplasia, ovarian carcinoma, serouscystadenocarcinoma, mucinous cystadenocarcinoma, granulosa-thecal celltumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma,intraepithelial carcinoma, adenocarcinoma, melanoma), vaginal clear cellcarcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubecarcinoma, acute and chronic myeloid leukemia, acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome, Hodgkin's disease,non-Hodgkin's lymphoma, malignant lymphoma, malignant melanoma, basalcell carcinoma, moles, dysplastic nevi, angioma, dermatofibroma,keloids, psoriasis, and neuroblastoma; in particular ovarian carcinoma,kidney cancer, prostate cancer, breast carcinoma, lymphomas, myeloma,bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellularcarcinoma, endometrial cancer, lung cancer, pancreatic cancer, gastriccancer and soft tissue sarcomas selected from rhabdomyosarcoma, synovialsarcoma and Ewing sarcoma; preferably pancreatic cancer, colon cancer,lung cancer, kidney cancer and ovarian carcinoma.

The compounds of the present invention may also be useful in thetreatment of other diseases or conditions related to the hyperactivityof MEK. Thus, as a further aspect, the invention relates to a method oftreatment of a disorder selected from: xenograft (cellos), skin, limb,organ or bone marrow transplant) rejection; osteoarthritis; rheumatoidarthritis; cystic fibrosis; complications of diabetes (includingdiabetic retinopathy and diabetic nephropathy); hepatomegaly;cardiomegaly; stroke (such as acute focal ischemic stroke and globalcerebral ischemia); heart failure; septic shock; asthma; chronicobstructive pulmonary disorder; Alzheimer's disease; and chronic orneuropathic pain.

The term “chronic pain” for purposes of the present invention includes,but is not limited to, idiopathic pain, and pain associated with chronicalcoholism, vitamin deficiency, uremia, or hypothyroidism. Chronic painis associated with numerous conditions including, but not limited to,inflammation, and post-operative pain.

As used herein, the term “neuropathic pain” is associated with numerousconditions which include, but are not limited to, inflammation,postoperative pain, phantom limb pain, burn pain, gout, trigeminalneuralgia, acute herpetic and postherpetic pain, causalgia, diabeticneuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crushinjury, constriction injury, tissue injury, limb amputation, and nerveinjury between the peripheral nervous system and the central nervoussystem.

Compounds of the invention may also be useful as antiviral agents fortreating viral infections such as HIV, hepatitis (B) virus (HBV) humanpapilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus(EBV).

Compounds of the invention may also be useful in the treatment ofrestenosis, psoriasis, allergic contact dermatitis, autoimmune disease,atherosclerosis and inflammatory bowel diseases, e.g. Crohn's diseaseand ulcerative colitis.

A MEK inhibitor of the present invention may be usefully combined withanother pharmacologically active compound, or with two or more otherpharmacologically active compounds, particularly in the treatment ofcancer. For example, a compound of the formula (I), or apharmaceutically acceptable salt thereof, as defined above, may beadministered simultaneously, sequentially or separately in combinationwith one or more agents selected from chemotherapy agents, for example,mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel,docetaxel, vincristine, vinblastine, vinorelbine or vinflunine, andother anticancer agents, e.g. cisplatin, 5-fluorouracil or5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine.

Such combinations may offer significant advantages, includingsynergistic activity, in therapy.

In certain embodiments, the present invention relates to theaforementioned method, wherein said compound is administeredparenterally.

In certain embodiments, the present invention relates to theaforementioned method, wherein said compound is administeredintramuscularly, intravenously, subcutaneously, orally, pulmonary,intrathecally, topically or intranasally.

In certain embodiments, the present invention relates to theaforementioned method, wherein said compound is administeredsystemically.

In certain embodiments, the present invention relates to theaforementioned method, wherein said patient is a mammal.

In certain embodiments, the present invention relates to theaforementioned method, wherein said patient is a primate.

In certain embodiments, the present invention relates to theaforementioned method, wherein said patient is a human.

In another aspect, the present invention relates to a method of treatingan MEK-mediated disorder, comprising the step of: administering to apatient in need thereof a therapeutically effective amount of achemothereutic agent in combination with a therapeutically effectiveamount of a compound of formula I as defined in the Summary of theInvention.

Pharmaceutical Compositions

In another aspect, the present invention provides pharmaceuticallyacceptable compositions which comprise a therapeutically-effectiveamount of one or more of the compounds described above, formulatedtogether with one or more pharmaceutically acceptable carriers(additives) and/or diluents. As described in detail below, thepharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) oral administration, for example,drenches (aqueous or non-aqueous solutions or suspensions), tablets,e.g., those targeted for buccal, sublingual, and systemic absorption,boluses, powders, granules, pastes for application to the tongue; (2)parenteral administration, for example, by subcutaneous, intramuscular,intravenous or epidural injection as, for example, a sterile solution orsuspension, or sustained-release formulation; (3) topical application,for example, as a cream, ointment, or a controlled-release patch orspray applied to the skin; (4) intravaginally or intrarectally, forexample, as a pessary, cream or foam; (5) sublingually; (6) ocularly;(7) transdermally; (8) nasally; (9) pulmonary; or (10) intrathecally. Inone embodiment, the pharmaceutical formulation comprises a soliddispersion having a compound of the present invention, orpharmaceutically acceptable salt thereof, as the active ingredientembedded in a polymer or mixture of polymers, optionally mixed with atleast one excipient (eg a surfactant). Examples of suitable polymers arePVP k30, PVP-VA 64, HPMC E3, HPMC-ASLF, HPMC P, Eudragit EPO, EudragitL100, Soluplus or PEG8000. Examples of suitable excipients are SLS,Cremophor EL, vitamine E TPGS, Poloxamer407, Poloxamer188 or SolutolHS15.

The phrase “therapeutically-effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect in at least a sub-population of cells in an animal ata reasonable benefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, manufacturing aid (e.g.,lubricant, talc magnesium, calcium or zinc stearate, or steric acid), orsolvent encapsulating material, involved in carrying or transporting thesubject compound from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically-acceptable carriers include: (1) sugars, suchas lactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

As set out above, certain embodiments of the present compounds maycontain a basic functional group, such as amino or alkylamino, and are,thus, capable of forming pharmaceutically-acceptable salts withpharmaceutically-acceptable acids. The term “pharmaceutically-acceptablesalts” in this respect, refers to the relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ in the administration vehicle or thedosage form manufacturing process, or by separately reacting a purifiedcompound of the invention in its free base form with a suitable organicor inorganic acid, and isolating the salt thus formed during subsequentpurification. Representative salts include the hydrobromide,hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,valerate, oleate, palmitate, stearate, laurate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonatesalts and the like. (See, for example, Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

The pharmaceutically acceptable salts of the subject compounds includethe conventional nontoxic salts or quaternary ammonium salts of thecompounds, e.g., from non-toxic organic or inorganic acids. For example,such conventional nontoxic salts include those derived from inorganicacids such as hydrochloride, hydrobromic, sulfuric, sulfamic,phosphoric, nitric, and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic, and the like.

In other cases, the compounds of the present invention may contain oneor more acidic functional groups and, thus, are capable of formingpharmaceutically-acceptable salts with pharmaceutically-acceptablebases. The term “pharmaceutically-acceptable salts” in these instancesrefers to the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present invention. These salts can likewise beprepared in situ in the administration vehicle or the dosage formmanufacturing process, or by separately reacting the purified compoundin its free acid form with a suitable base, such as the hydroxide,carbonate or bicarbonate of a pharmaceutically-acceptable metal cation,with ammonia, or with a pharmaceutically-acceptable organic primary,secondary or tertiary amine Representative alkali or alkaline earthsalts include the lithium, sodium, potassium, calcium, magnesium, andaluminum salts and the like. Representative organic amines useful forthe formation of base addition salts include ethylamine, diethylamine,ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.(See, for example, Berge et al., supra)

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.Generally, out of one hundred percent, this amount will range from about0.1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present invention. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentinvention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-shelled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, oral, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient, when used for the indicated analgesic effects,will range from about 0.0001 to about 100 mg per kilogram of body weightper day.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. Preferred dosing is one administrationper day.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical formulation (composition).

The compounds according to the invention may be formulated foradministration in any convenient way for use in human or veterinarymedicine, by analogy with other pharmaceuticals.

In another aspect, the present invention provides pharmaceuticallyacceptable compositions which comprise a therapeutically-effectiveamount of one or more of the subject compounds, as described above,formulated together with one or more pharmaceutically acceptablecarriers (additives) and/or diluents. As described in detail below, thepharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) oral administration, for example,drenches (aqueous or non-aqueous solutions or suspensions), tablets,boluses, powders, granules, pastes for application to the tongue; (2)parenteral administration, for example, by subcutaneous, intramuscularor intravenous injection as, for example, a sterile solution orsuspension; (3) topical application, for example, as a cream, ointmentor spray applied to the skin, lungs, or mucous membranes; or (4)intravaginally or intrarectally, for example, as a pessary, cream orfoam; (5) sublingually or buccally; (6) ocularly; (7) transdermally; or(8) nasally.

The term “treatment” is intended to encompass also prophylaxis, therapyand cure.

The patient receiving this treatment is any animal in need, includingprimates, in particular humans, and other mammals such as equines,cattle, swine and sheep; and poultry and pets in general.

The compound of the invention can be administered as such or inadmixtures with pharmaceutically acceptable carriers and can also beadministered in conjunction with antimicrobial agents such aspenicillins, cephalosporins, aminoglycosides and glycopeptides.Conjunctive therapy, thus includes sequential, simultaneous and separateadministration of the active compound in a way that the therapeuticaleffects of the first administered one is not entirely disappeared whenthe subsequent is administered.

Microemulsification technology can improve bioavailability of somelipophilic (water insoluble) pharmaceutical agents. Examples includeTrimetrine (Dordunoo, S. K., et al., Drug Development and IndustrialPharmacy, 17(12), 1685-1713, 1991 and REV 5901 (Sheen, P. C., et al., JPharm Sci 80(7), 712-714, 1991). Among other things, microemulsificationprovides enhanced bioavailability by preferentially directing absorptionto the lymphatic system instead of the circulatory system, which therebybypasses the liver, and prevents destruction of the compounds in thehepatobiliary circulation.

While all suitable amphiphilic carriers are contemplated, the presentlypreferred carriers are generally those that haveGenerally-Recognized-as-Safe (GRAS) status, and that can both solubilizethe compound of the present invention and microemulsify it at a laterstage when the solution comes into a contact with a complex water phase(such as one found in human gastrointestinal tract). Usually,amphiphilic ingredients that satisfy these requirements have HLB(hydrophilic to lipophilic balance) values of 2-20, and their structurescontain straight chain aliphatic radicals in the range of C-6 to C-20.Examples are polyethylene-glycolized fatty glycerides and polyethyleneglycols.

Commercially available amphiphilic carriers are particularlycontemplated, including Gelucire-series, Labrafil, Labrasol, orLauroglycol (all manufactured and distributed by Gattefosse Corporation,Saint Priest, France), PEG-mono-oleate, PEG-di-oleate, PEG-mono-laurateand di-laurate, Lecithin, Polysorbate 80, etc (produced and distributedby a number of companies in USA and worldwide).

Hydrophilic polymers suitable for use in the present invention are thosewhich are readily water-soluble, can be covalently attached to avesicle-forming lipid, and which are tolerated in vivo without toxiceffects (i.e., are biocompatible). Suitable polymers includepolyethylene glycol (PEG), polylactic (also termed polylactide),polyglycolic acid (also termed polyglycolide), a polylactic-polyglycolicacid copolymer, and polyvinyl alcohol. Preferred polymers are thosehaving a molecular weight of from about 100 or 120 daltons up to about5,000 or 10,000 daltons, and more preferably from about 300 daltons toabout 5,000 daltons. In a particularly preferred embodiment, the polymeris polyethyleneglycol having a molecular weight of from about 100 toabout 5,000 daltons, and more preferably having a molecular weight offrom about 300 to about 5,000 daltons. In a particularly preferredembodiment, the polymer is polyethyleneglycol of 750 daltons (PEG(750)).Polymers may also be defined by the number of monomers therein; apreferred embodiment of the present invention utilizes polymers of atleast about three monomers, such PEG polymers consisting of threemonomers (approximately 150 daltons).

Other hydrophilic polymers which may be suitable for use in the presentinvention include polyvinylpyrrolidone, polymethoxazoline,polyethyloxazoline, polyhydroxypropyl methacrylamide,polymethacrylamide, polydimethylacrylamide, and derivatized cellulosessuch as hydroxymethylcellulose or hydroxyethylcellulose.

In certain embodiments, a formulation of the present invention comprisesa biocompatible polymer selected from the group consisting ofpolyamides, polycarbonates, polyalkylenes, polymers of acrylic andmethacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes,polyurethanes and co-polymers thereof, celluloses, polypropylene,polyethylenes, polystyrene, polymers of lactic acid and glycolic acid,polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid),poly(lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronicacids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.

Cyclodextrins are cyclic oligosaccharides, consisting of 6, 7 or 8glucose units, designated by the Greek letter .alpha., .beta. or.gamma., respectively. Cyclodextrins with fewer than six glucose unitsare not known to exist. The glucose units are linked byalpha-1,4-glucosidic bonds. As a consequence of the chair conformationof the sugar units, all secondary hydroxyl groups (at C-2, C-3) arelocated on one side of the ring, while all the primary hydroxyl groupsat C-6 are situated on the other side. As a result, the external facesare hydrophilic, making the cyclodextrins water-soluble. In contrast,the cavities of the cyclodextrins are hydrophobic, since they are linedby the hydrogen of atoms C-3 and C-5, and by ether-like oxygens. Thesematrices allow complexation with a variety of relatively hydrophobiccompounds, including, for instance, steroid compounds such as17.beta.-estradiol (see, e.g., van Uden et al. Plant Cell Tiss. Org.Cult. 38:1-3-113 (1994)). The complexation takes place by Van der Waalsinteractions and by hydrogen bond formation. For a general review of thechemistry of cyclodextrins, see, Wenz, Agnew. Chem. Int. Ed. Engl.,33:803-822 (1994).

The physico-chemical properties of the cyclodextrin derivatives dependstrongly on the kind and the degree of substitution. For example, theirsolubility in water ranges from insoluble (e.g.,triacetyl-beta-cyclodextrin) to 147% soluble (w/v)(G-2-beta-cyclodextrin). In addition, they are soluble in many organicsolvents. The properties of the cyclodextrins enable the control oversolubility of various formulation components by increasing or decreasingtheir solubility.

Numerous cyclodextrins and methods for their preparation have beendescribed. For example, Parmeter (I), et al. (U.S. Pat. No. 3,453,259)and Gramera, et al. (U.S. Pat. No. 3,459,731) described electroneutralcyclodextrins. Other derivatives include cyclodextrins with cationicproperties [Parmeter (II), U.S. Pat. No. 3,453,257], insolublecrosslinked cyclodextrins (Solms, U.S. Pat. No. 3,420,788), andcyclodextrins with anionic properties [Parmeter (III), U.S. Pat. No.3,426,011]. Among the cyclodextrin derivatives with anionic properties,carboxylic acids, phosphorous acids, phosphinous acids, phosphonicacids, phosphoric acids, thiophosphonic acids, thiosulphinic acids, andsulfonic acids have been appended to the parent cyclodextrin [see,Parmeter (III), supra]. Furthermore, sulfoalkyl ether cyclodextrinderivatives have been described by Stella, et al. (U.S. Pat. No.5,134,127).

Liposomes consist of at least one lipid bilayer membrane enclosing anaqueous internal compartment. Liposomes may be characterized by membranetype and by size. Small unilamellar vesicles (SUVs) have a singlemembrane and typically range between 0.02 and 0.05 μm in diameter; largeunilamellar vesicles (LUVS) are typically larger than 0.05 μmOligolamellar large vesicles and multilamellar vesicles have multiple,usually concentric, membrane layers and are typically larger than 0.1μm. Liposomes with several nonconcentric membranes, i.e., severalsmaller vesicles contained within a larger vesicle, are termedmultivesicular vesicles.

One aspect of the present invention relates to formulations comprisingliposomes containing a compound of the present invention, where theliposome membrane is formulated to provide a liposome with increasedcarrying capacity. Alternatively or in addition, the compound of thepresent invention may be contained within, or adsorbed onto, theliposome bilayer of the liposome. The compound of the present inventionmay be aggregated with a lipid surfactant and carried within theliposomes internal space; in these cases, the liposome membrane isformulated to resist the disruptive effects of the activeagent-surfactant aggregate.

According to one embodiment of the present invention, the lipid bilayerof a liposome contains lipids derivatized with polyethylene glycol(PEG), such that the PEG chains extend from the inner surface of thelipid bilayer into the interior space encapsulated by the liposome, andextend from the exterior of the lipid bilayer into the surroundingenvironment.

Active agents contained within liposomes of the present invention are insolubilized form. Aggregates of surfactant and active agent (such asemulsions or micelles containing the active agent of interest) may beentrapped within the interior space of liposomes according to thepresent invention. A surfactant acts to disperse and solubilize theactive agent, and may be selected from any suitable aliphatic,cycloaliphatic or aromatic surfactant, including but not limited tobiocompatible lysophosphatidylcholines (LPCs) of varying chain lengths(for example, from about C.sub.14 to about C.sub.20).Polymer-derivatized lipids such as PEG-lipids may also be utilized formicelle formation as they will act to inhibit micelle/membrane fusion,and as the addition of a polymer to surfactant molecules decreases theCMC of the surfactant and aids in micelle formation. Preferred aresurfactants with CMCs in the micromolar range; higher CMC surfactantsmay be utilized to prepare micelles entrapped within liposomes of thepresent invention, however, micelle surfactant monomers could affectliposome bilayer stability and would be a factor in designing a liposomeof a desired stability.

Liposomes according to the present invention may be prepared by any of avariety of techniques that are known in the art. See, e.g., U.S. Pat.No. 4,235,871; Published PCT applications WO 96/14057; New RRC,Liposomes: A practical approach, IRL Press, Oxford (1990), pages 33-104;Lasic D D, Liposomes from physics to applications, Elsevier SciencePublishers BV, Amsterdam, 1993.

For example, liposomes of the present invention may be prepared bydiffusing a lipid derivatized with a hydrophilic polymer into preformedliposomes, such as by exposing preformed liposomes to micelles composedof lipid-grafted polymers, at lipid concentrations corresponding to thefinal mole percent of derivatized lipid which is desired in theliposome. Liposomes containing a hydrophilic polymer can also be formedby homogenization, lipid-field hydration, or extrusion techniques, asare known in the art.

In one aspect of the present invention, the liposomes are prepared tohave substantially homogeneous sizes in a selected size range. Oneeffective sizing method involves extruding an aqueous suspension of theliposomes through a series of polycarbonate membranes having a selecteduniform pore size; the pore size of the membrane will correspond roughlywith the largest sizes of liposomes produced by extrusion through thatmembrane. See e.g., U.S. Pat. No. 4,737,323 (Apr. 12, 1988).

The release characteristics of a formulation of the present inventiondepend on the encapsulating material, the concentration of encapsulateddrug, and the presence of release modifiers. For example, release can bemanipulated to be pH dependent, for example, using a pH sensitivecoating that releases only at a low pH, as in the stomach, or a higherpH, as in the intestine. An enteric coating can be used to preventrelease from occurring until after passage through the stomach. Multiplecoatings or mixtures of cyanamide encapsulated in different materialscan be used to obtain an initial release in the stomach, followed bylater release in the intestine. Release can also be manipulated byinclusion of salts or pore forming agents, which can increase wateruptake or release of drug by diffusion from the capsule. Excipientswhich modify the solubility of the drug can also be used to control therelease rate. Agents which enhance degradation of the matrix or releasefrom the matrix can also be incorporated. They can be added to the drug,added as a separate phase (i.e., as particulates), or can beco-dissolved in the polymer phase depending on the compound. In allcases the amount should be between 0.1 and thirty percent (w/w polymer).Types of degradation enhancers include inorganic salts such as ammoniumsulfate and ammonium chloride, organic acids such as citric acid,benzoic acid, and ascorbic acid, inorganic bases such as sodiumcarbonate, potassium carbonate, calcium carbonate, zinc carbonate, andzinc hydroxide, and organic bases such as protamine sulfate, spermine,choline, ethanolamine, diethanolamine, and triethanolamine andsurfactants such as Tween® and Pluronic®. Pore forming agents which addmicrostructure to the matrices (i.e., water soluble compounds such asinorganic salts and sugars) are added as particulates. The range shouldbe between one and thirty percent (w/w polymer).

Uptake can also be manipulated by altering residence time of theparticles in the gut. This can be achieved, for example, by coating theparticle with, or selecting as the encapsulating material, a mucosaladhesive polymer. Examples include most polymers with free carboxylgroups, such as chitosan, celluloses, and especially polyacrylates (asused herein, polyacrylates refers to polymers including acrylate groupsand modified acrylate groups such as cyanoacrylates and methacrylates).

Pharmaceutical Combinations

The invention especially relates to the use of a compound of the formulaI (or a pharmaceutical composition comprising a compound of the formulaI) in the treatment of one or more of the diseases mentioned herein;wherein the response to treatment is beneficial as demonstrated, forexample, by the partial or complete removal of one or more of thesymptoms of the disease up to complete cure or remission.

A compound of formula (I) can also be used in combination with otherantiproliferative compounds. Such antiproliferative compounds include,but are not limited to aromatase inhibitors; antiestrogens;topoisomerase I inhibitors; topoisomerase II inhibitors; microtubuleactive compounds; alkylating compounds; histone deacetylase inhibitors;compounds which induce cell differentiation processes; cyclooxygenaseinhibitors; MMP inhibitors; mTOR inhibitors, such as RAD001;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; bisphosphonates;biological response modifiers; antiproliferative antibodies, such asHCD122; heparanase inhibitors; inhibi-tors of Ras oncogenic isoforms;telomerase inhibitors; proteasome inhibitors; compounds used in thetreatment of hematologic malignancies, such as FLUDARABINE; compoundswhich target, decrease or inhibit the activity of Flt-3, such as PKC412;Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics and AUY922; temozolomide (TEMODAL®); kinesin spindleprotein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline,or pentamidine/chlorpromazine from CombinatoRx; PI3K inhibitors, such asBEZ235, BKM120 [i.e.

5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine]or BYL719 [i.e.(S)—N-1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide];in particular BEZ235; preferably BKM120 or BYL719; RAF inhibitors, suchas LGX818 or RAF265; MEK inhibitors such as ARRY142886 from ArrayPioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, leucovorin,EDG binders, antileukemia compounds, ribonucleotide reductaseinhibittors, S-adenosylmethionine decarboxylase inhibitors,antiproliferative antibodies or other chemotherapeutic compounds.Further, alternatively or in addition they may be used in combinationwith other tumor treatment approaches, including surgery, ionizingradiation, photodynamic therapy, implants, e.g. with corticosteroids,hormones, or they may be used as radiosensitizers. Also, inanti-inflammatory and/or antiproliferative treatment, combination withanti-inflammatory drugs is included. Combination is also possible withantihistamine drug substances, bronchodilatatory drugs, NSAID orantagonists of chemokine receptors.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits the estrogen production, i.e. the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane can be administered,e.g., in the form as it is marketed, e.g. under the trademark AROMASIN.Formestane can be administered, e.g., in the form as it is marketed,e.g. under the trademark LENTARON. Fadrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark AFEMA.Anastrozole can be administered, e.g., in the form as it is marketed,e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR.Aminoglutethimide can be administered, e.g., in the form as it ismarketed, e.g. under the trademark ORIMETEN. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, e.g. breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g. under the trademark NOLVADEX.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA. Fulvestrant can be formulatedas disclosed in U.S. Pat. No. 4,659,516 or it can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FASLODEX. Acombination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, e.g. breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (CASODEX), which canbe formulated, e.g. as disclosed in U.S. Pat. No. 4,636,505.

The term “gonadorelin agonist” as used herein includes, but is notlimited to abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g. under the trademark ZOLADEX. Abarelixcan be formulated, e.g. as disclosed in U.S. Pat. No. 5,843,901.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148 (compound A1 in WO99/17804). Irinotecan can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark CAMPTOSAR. Topotecan can be administered, e.g., in the form asit is marketed, e.g. under the trademark HYCAMTIN.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, e.g. CAELYX), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide can be administered, e.g. in the form as it is marketed, e.g.under the trademark ETOPOPHOS. Teniposide can be administered, e.g. inthe form as it is marketed, e.g. under the trademark VM 26-BRISTOL.Doxorubicin can be administered, e.g. in the form as it is marketed,e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark FARMORUBICIN. Idarubicin can be administered, e.g. in the formas it is marketed, e.g. under the trademark ZAVEDOS. Mitoxantrone can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark NOVANTRON.

The term “microtubule active compound” relates to microtubulestabilizing, microtubule destabilizing compounds and microtublinpolymerization inhibitors including, but not limited to taxanes, e.g.paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especiallyvinblastine sulfate, vincristine especially vincristine sulfate, andvinorelbine, discodermolides, cochicine and epothilones and derivativesthereof, e.g. epothilone B or D or derivatives thereof. Paclitaxel maybe administered e.g. in the form as it is marketed, e.g. TAXOL.Docetaxel can be administered, e.g., in the form as it is marketed, e.g.under the trademark TAXOTERE. Vinblastine sulfate can be administered,e.g., in the form as it is marketed, e.g. under the trademark VINBLASTINR.P. Vincristine sulfate can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FARMISTIN. Discodermolide can beobtained, e.g., as disclosed in U.S. Pat. No. 5,010,099. Also includedare Epothilone derivatives which are disclosed in WO 98/10121, U.S. Pat.No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO00/31247. Especially preferred are Epothilone A and/or B.

The term “alkylating compound” as used herein includes, but is notlimited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNUor Gliadel). Cyclophosphamide can be administered, e.g., in the form asit is marketed, e.g. under the trademark CYCLOSTIN. Ifosfamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HOLOXAN.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes compounds such as LDH589disclosed in WO 02/22577, especiallyN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamideand pharmaceutically acceptable salts thereof. It further especiallyincludes Suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabinecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark XELODA. Gemcitabine can be administered, e.g., in the form asit is marketed, e.g. under the trademark GEMZAR.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity”; or a “protein or lipid phosphatase activity”; or “furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, for example:

-   -   a) compounds targeting, decreasing or inhibiting the activity of        the platelet-derived growth factor-receptors (PDGFR), such as        compounds which target, decrease or inhibit the activity of        PDGFR, especially compounds which inhibit the PDGF receptor,        e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib,        SU101, SU6668 and GFB-111;    -   b) compounds targeting, decreasing or inhibiting the activity of        the fibroblast growth factor-receptors (FGFR);    -   c) compounds targeting, decreasing or inhibiting the activity of        the insulin-like growth factor receptor I (IGF-IR), such as        compounds which target, decrease or inhibit the activity of        IGF-IR, especially compounds which inhibit the kinase activity        of IGF-I receptor, such as those compounds disclosed in WO        02/092599, or antibodies that target the extracellular domain of        IGF-I receptor or its growth factors;    -   d) compounds targeting, decreasing or inhibiting the activity of        the Trk receptor tyrosine kinase family, or ephrin B4        inhibitors;    -   e) compounds targeting, decreasing or inhibiting the activity of        the Axl receptor tyrosine kinase family;    -   f) compounds targeting, decreasing or inhibiting the activity of        the Ret receptor tyrosine kinase;    -   g) compounds targeting, decreasing or inhibiting the activity of        the Kit/SCFR receptor tyrosine kinase, i.e C-kit receptor        tyrosine kinases —(part of the PDGFR family), such as compounds        which target, decrease or inhibit the activity of the c-Kit        receptor tyrosine kinase family, especially compounds which        inhibit the c-Kit receptor, e.g. imatinib;    -   h) compounds targeting, decreasing or inhibiting the activity of        members of the c-Abl family, their gene-fusion products (e.g.        BCR-Abl kinase) and mutants, such as compounds which target        decrease or inhibit the activity of c-AbI family members and        their gene fusion products, e.g. a N-phenyl-2-pyrimidine-amine        derivative, e.g. imatinib or nilotinib (AMN107); PD180970;        AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib        (BMS-354825)    -   i) compounds targeting, decreasing or inhibiting the activity of        members of the protein kinase C (PKC) and Raf family of        serine/threonine kinases, members of the MEK, ERK, SRC, JAK,        FAK, PDK1, PKB/Akt, and Ras/MAPK family members, such as members        of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK family        members, and/or members of the cyclin-dependent kinase family        (CDK) and are especially those staurosporine derivatives        disclosed in U.S. Pat. No. 5,093,330, e.g. midostaurin; examples        of further compounds include e.g. UCN-01, safingol, BAY 43-9006,        Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432;        GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds        such as those disclosed in WO 00/09495; FTIs; BEZ235 (a PI3K        inhibitor) or AT7519 (CDK inhibitor); in particular compounds        targeting, decreasing or inhibiting the activity of members of        the protein kinase C (PKC) and Raf family of serine/threonine        kinases, members of the MEK, ERK, SRC, JAK, FAK, PDK1, PKB/Akt,        and Ras/MAPK family members, and/or members of the        cyclin-dependent kinase family (CDK) and are especially those        staurosporine derivatives disclosed in U.S. Pat. No. 5,093,330,        e.g. midostaurin; examples of further compounds include e.g.        UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine;        Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;        LY333531/LY379196; isochinoline compounds such as those        disclosed in WO 00/09495; Dabrafenib, Vemurafenib, Encorafenib;        FTIs; BEZ235 (a PI3K inhibitor) or AT7519 (CDK inhibitor) or        NVP-LEE011 (i.e.,        7-cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide);        GDC-0994 (i.e.,        (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one)        or SCH900353 or BVD-523 (i.e.,        (S)-4-(5-chloro-2-(isopropylamino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide);        preferably Dabrafenib, NVP-LEE011 (i.e.,        7-cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide)        or Encorafenib.    -   j) compounds targeting, decreasing or inhibiting the activity of        protein-tyrosine kinase inhibitors, such as compounds which        target, decrease or inhibit the activity of protein-tyrosine        kinase inhibitors include imatinib mesylate (GLEEVEC) or        tyrphostin. A tyrphostin is preferably a low molecular weight        (Mr<1500) compound, or a pharmaceutically acceptable salt        thereof, especially a compound selected from the        benzylidenemalonitrile class or the S-arylbenzenemalonirile or        bisubstrate quinoline class of compounds, more especially any        compound selected from the group consisting of Tyrphostin        A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748;        Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+)        enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957        and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic        acid adamantyl ester; NSC 680410, adaphostin);    -   k) compounds targeting, decreasing or inhibiting the activity of        the epidermal growth factor family of receptor tyrosine kinases        (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their        mutants, such as compounds which target, decrease or inhibit the        activity of the epidermal growth factor receptor family are        especially compounds, proteins or antibodies which inhibit        members of the EGF receptor tyrosine kinase family, e.g. EGF        receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related        ligands, and are in particular those compounds, proteins or        monoclonal antibodies generically and specifically disclosed in        WO 97/02266, e.g. the compound of ex. 39, or in EP 0 564 409, WO        99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063,        U.S. Pat. No. 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688,        WO 97/38983 and, especially, WO 96/30347 (e.g. compound known as        CP 358774), WO 96/33980 (e.g. compound ZD 1839) and WO 95/03283        (e.g. compound ZM105180); e.g. trastuzumab (Herceptin™),        cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, CI-1033,        EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or        E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives which are        disclosed in WO 03/013541; and    -   1) compounds targeting, decreasing or inhibiting the activity of        the c-Met receptor, such as compounds which target, decrease or        inhibit the activity of c-Met, especially compounds which        inhibit the kinase activity of c-Met receptor, or antibodies        that target the extracellular domain of c-Met or bind to HGF.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (THALOMID) and TNP-470.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, e.g. okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes are e.g. retinoicacid, α-γ- or δ-tocopherol or α-γ- or δ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, e.g. Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, e.g.5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. “Etridonic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark DIDRONEL. “Clodronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark BONEFOS. “Tiludronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark SKELID. “Pamidronic acid” can be administered, e.g.in the form as it is marketed, e.g. under the trademark AREDIA™.“Alendronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FOSAMAX. “Ibandronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONDRANAT. “Risedronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ACTONEL. “Zoledronicacid” can be administered, e.g. in the form as it is marketed, e.g.under the trademark ZOMETA.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779and ABT578; preferably everolimus.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88.

The term “biological response modifier” as used herein refers to alymphokine or interferons, e.g. interferon γ.

The term “inhibitor of Ras oncogenic isoforms”, e.g. H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras e.g. a “farnesyl transferaseinhibitor” e.g. L-744832, DK8G557 or R115777 (Zarnestra).

The term “telomerase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of telomerase. Compounds whichtarget, decrease or inhibit the activity of telomerase are especiallycompounds which inhibit the telomerase receptor, e.g. telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase are e.g. bengamide or a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasome includee.g. Bortezomid (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors e.g. compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitorse.g. compounds which target, decrease or inhibit anaplastic lymphomakinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,e.g. PKC412, TKI258, midostaurin, a staurosporine derivative, SU11248and MLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90 e.g., 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors. An example HSP90 inhibitor isAUY922.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1,erbitux,bevacizumab (Avastin™), rituximab (Rituxan), PRO64553 (anti-CD40), 2C4Antibody and HCD122 antibody (anti-CD40). By antibodies is meant e.g.intact monoclonal antibodies, polyclonal antibodies, multispecificantibodies formed from at least 2 intact antibodies, and antibodiesfragments so long as they exhibit the desired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of formula(I) can be used in combination with standard leukemia therapies,especially in combination with therapies used for the treatment of AML.In particular, compounds of formula (I) can be administered incombination with, e.g., farnesyl transferase inhibitors and/or otherdrugs useful for the treatment of AML, such as Daunorubicin, Adriamycin,Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum andPKC412.

The term “antileukemic compounds” includes, for example, Ara-C, apyrimidine analog, which is the 2′-alpha-hydroxy ribose (arabinoside)derivative of deoxycytidine. Also included is the purine analog ofhypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.

Compounds which target, decrease or inhibit activity of histonedeacetylase (HDAC) inhibitors such as sodium butyrate andsuberoylanilide hydroxamic acid (SAHA) inhibit the activity of theenzymes known as histone deacetylases. Specific HDAC inhibitors includeMS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compoundsdisclosed in U.S. Pat. No. 6,552,065, in particular,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]-methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt.

Somatostatin receptor antagonists as used herein refers to compoundswhich target, treat or inhibit the somatostatin receptor such asoctreotide, and SOM230 (pasireotide).

Tumor cell damaging approaches refer to approaches such as ionizingradiation. The term “ionizing radiation” referred to above andhereinafter means ionizing radiation that occurs as eitherelectromagnetic rays (such as X-rays and gamma rays) or particles (suchas alpha and beta particles). Ionizing radiation is provided in, but notlimited to, radiation therapy and is known in the art. See Hellman,Principles of Radiation Therapy, Cancer, in Principles and Practice ofOncology, Devita et al., Eds., 4^(th) Edition, Vol. 1, pp. 248-275(1993).

The term “EDG binders” as used herein refers a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720.

The term “ribonucleotide reductase inhibitors” refers to pyrimidine orpurine nucleoside analogs including, but not limited to, fludarabineand/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil,cladribine, 6-mercaptopurine (especially in combination with ara-Cagainst ALL) and/or pentostatin. Ribonucleotide reductase inhibitors areespecially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives,such as PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned inNandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994).

The term “S-adenosylmethionine decarboxylase inhibitors” as used hereinincludes, but is not limited to the compounds disclosed in U.S. Pat. No.5,461,076.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF disclosed in WO 98/35958, e.g.1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof, e.g. the succinate, or in WO 00/09495, WO00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; thoseas described by Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218(1999); Yuan et al., Proc Natl Acad Sci USA, Vol. 93, pp. 14765-14770(1996); Zhu et al., Cancer Res, Vol. 58, pp. 3209-3214 (1998); andMordenti et al., Toxicol Pathol, Vol. 27, No. 1, pp. 14-21 (1999); in WO00/37502 and WO 94/10202; ANGIOSTATIN, described by O'Reilly et al.,Cell, Vol. 79, pp. 315-328 (1994); ENDOSTATIN, described by O'Reilly etal., Cell, Vol. 88, pp. 277-285 (1997); anthranilic acid amides; ZD4190;ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies oranti-VEGF receptor antibodies, e.g. rhuMAb and RHUFab, VEGF aptamer e.g.Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™)

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy includes treatment withcompounds, such as e.g. VISUDYNE and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such as e.g.fluocinolone, dexamethasone.

“Other chemotherapeutic compounds” include, but are not limited to,plant alkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The structure of the active compounds identified by code nos., genericor trade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

Some combinations might be particularly useful for the treatment ofcertain types of proliferative diseases. The following non-exhaustivelist indicates some preferred combinations and the respective diseases:a compound of the present invention in combination with an inhibitor ofEGFR (e.g. Iressa™), in particular for the treatment of NSCLC; acompound of the present invention in combination with an inhibitor ofPI-3K, such as BEZ235 (CAS No. 915019-65-7) from Novartis, in particularfor the treatment of Nasopharyngeal carcinoma (NPC) and some othercancers; a compound of the present invention in combination with aninhibitor of mTOR; a compound of the present invention in combinationwith a tyrosine protein kinase and/or Raf inhibitor such as Sorafenib,in particular for the treatment of primary kidney cancer (advanced renalcell carcinoma) and advanced primary liver cancer (hepatocellularcarcinoma); a compound of the present invention in combination with anVEGFR inhibitor such as PTK787 or an antibody against the ligand VEGFsuch as Avastin®; a compound of the present invention in combinationwith an PDGFR inhibitor, e.g. imatinib (STI571 or Glivec®); a compoundof the present invention in combination with an mTOR inhibitors, such asrapamycin and everolimus (RAD001).

In one embodiment, the other therapeutic agent is selected from: an EGFRinhibitor such as Iressa™; Raf inhibitor such as Sorafenib; PI-3Kinhibitor such as BEZ235 (CAS No. 915019-65-7); VEGFR inhibitor such asPTK787; VEGF antibody such as Avastin®; PDGFR inhibitor such as STI571(Glivec®); mTOR inhibitors such as rapamycin and everolimus; aromataseinhibitor such as letrozole (Femara®) or anastrozole; microtubule activecompound such as paclitaxel or an epothilone; antineoplasticantimetabolite such as gemcitabine or capecitabine; platin compoundssuch as carboplatin or cis-platin; bisphosphonates such as AREDIAO orZOMETAO; and HER2 antibodies such as trastuzumab.

None of the quotations of references made within the present disclosureis to be understood as an admission that the references cited are priorart that would negatively affect the patentability of the presentinvention.

Processes for Making Compounds of the Invention

Compounds of the invention can be prepared according to reaction Scheme1, wherein n, R1, R2, R5, R4 and R3a are as defined for a compound offormula (I) herein and R3 is R3a and optionally comprises a hydroxyl oran amino protecting group.

In the present application the term “nitrogen protecting group”generally comprises any group which is capable of reversibly protectinga nitrogen functionality, preferably an amino and/or amidefunctionality. The term “hydroxylprotecting group” generally comprisesany group which is capable of reversibly protecting the hydroxylfunctionality. Suitable nitrogen protecting groups andhydroxylprotecting groups are described e.g. in the relevant chapters ofstandard reference works such as J. F. W. McOmie, “Protective Groups inOrganic Chemistry”, Plenum Press, London and New York 1973; T. W. Greeneand P. G. M. Wuts, “Greene's Protective Groups in Organic Synthesis”,Fourth Edition, Wiley, New York 2007; in “The Peptides”; Volume 3(editors: E. Gross and J. Meienhofer), Academic Press, London and NewYork 1981, and in “Methoden der organischen Chemie” (Methods of OrganicChemistry), Houben Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag,Stuttgart 1974.

The present invention also includes processes for the preparation ofcompounds of the invention. In the reactions described, it can benecessary to protect reactive functional groups, for example hydroxy,amino, imino, thio or carboxy groups, where these are desired in thefinal product, to avoid their unwanted participation in the reactions.Conventional protecting groups can be used in accordance with standardpractice, for example, see T. W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Chemistry”, John Wiley and Sons, 1991.

Compounds of Formula I can be prepared by proceeding as in the followingReaction Scheme 2:

in which R₁, R₂, R_(3a), R₄ and R₅ are as defined for Formula I in theSummary of the Invention and X represents a group, such as a leavinggroup, selected from bromine, chlorine, or the like.

A compound of Formula I can be prepared by reacting a compound offormula (2) with a compound of formula (3) in the presence of a suitablebase (such as TEA, DIPEA, K₂CO₃, or the like), a suitable couplingreagent (such as EDCI, HOBt, HATU, or the like), a suitable reactant(such as alkyl halides, acid chlorides, sulfonyl chlorides, carbamoylchlorides, sulfamoyl chlorides, isocyanate or the like, in particularsuch as alkyl halides, acid chlorides, sulfonyl chlorides) and asuitable solvent (such as dichlormethane, THF, ACN, DMF, or the like).The reaction takes place at about 0° C. to about 100° C. and can takefrom about 1 to about 24 hours to complete.

6-Bromo-4-chloro-7-fluoro-3-nitroquinoline (1.3 in Scheme 1) is preparedaccording to the synthesis described in WO 200505423, Example 54b. Thediarylether boronic acid used in the cross-coupling Step-4 of Scheme 1can be prepared according to the general scheme 3 below, either startingfrom commercially available phenol 3.1 or biarylether halide 3.2.

Detailed examples of the synthesis of compounds of Formula I can befound in the Examples, infra. Steps 1 to 12 in Scheme 1 and Steps 12 and13 in Scheme 3 refer to specific reaction conditions which are describedfor example in the Experimental section herein and in standard referenceworks, such as in the relevant chapters in Richard C. Larock,“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations”, Second Edition, Wiley-VCH Verlag GmbH, 2000 and in T. W.Greene and P. G. M. Wuts, “Greene's Protective Groups in OrganicSynthesis”, Fourth Edition, Wiley, New York 2007.

Additional Processes for Making Compounds of the Invention

A compound of the invention can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase.

Compounds of the formula I can also be modified by appending appropriatefunctionalities to enhance selective biological properties.Modifications of this kind are known in the art and include those thatincrease penetration into a given biological system (e.g. blood,lymphatic system, central nervous system, testis), increasebioavailability, increase solubility to allow parenteral administration(e.g. injection, infusion), alter metabolism and/or alter the rate ofsecretion. Examples of this type of modifications include but are notlimited to esterification, e.g. with polyethylene glycols,derivatisation with pivaloyloxy or fatty acid substituents, conversionto carbamates, hydroxylation of aromatic rings and heteroatomsubstitution in aromatic rings. Whereever compounds of the formula I,and/or N-oxides, tautomers and/or (preferably pharmaceuticallyacceptable) salts thereof are mentioned, this comprises such modifiedformulae, while preferably the molecules of the formula I, theirN-oxides, their tautomers and/or their salts are meant.

Alternatively, the salt forms of the compounds of the invention can beprepared using salts of the starting materials or intermediates. In viewof the close relationship between the novel compounds of the formula Iin free form and those in the form of their salts, including those saltsthat can be used as intermediates, for example in the purification oridentification of the novel compounds, any reference to the compounds ora compound of the formula I hereinbefore and hereinafter is to beunderstood as referring to the compound in free form and/or also to oneor more salts thereof, as appropriate and expedient, as well as to oneor more solvates, e.g. hydrates.

Salts are formed, for example, as acid addition salts, preferably withorganic or inorganic acids, from compounds of formula I with a basicnitrogen atom, especially the pharmaceutically acceptable salts.Suitable inorganic acids are, for example, halogen acids, such ashydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organicacids are, for example, carboxylic, phosphonic, sulfonic or sulfamicacids, for example acetic acid, propionic acid, octanoic acid, decanoicacid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid,succinic acid, malonic acid, adipic acid, pimelic acid, suberic acid,azelaic acid, malic acid, tartaric acid, citric acid, amino acids, suchas glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid,methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylicacid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalicacid, phenylacetic acid, mandelic acid, cinnamic acid, methane- orethane-sulfonic acid, 2-hydroxyethanesulfonic acid,ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-toluenesulfonicacid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2- or3-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid,dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- orN-propyl-sulfamic acid, or other organic protonic acids, such asascorbic acid.

For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. For therapeutic use, only pharmaceutically acceptablesalts or free compounds are employed (where applicable in the form ofpharmaceutical preparations), and these are therefore preferred.

The free acid or free base forms of the compounds of the invention canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the invention in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc.,1999.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. While resolution of enantiomers can be carried outusing covalent diastereomeric derivatives of the compounds of theinvention, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chromatography,or preferably, by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981.

In summary, the compounds of Formula I can be made by a process, whichinvolves:

-   -   (a) those of reaction scheme I; and    -   (b) optionally converting a compound of the invention into a        pharmaceutically acceptable salt;    -   (c) optionally converting a salt form of a compound of the        invention to a non-salt form;    -   (d) optionally converting an unoxidized form of a compound of        the invention into a pharmaceutically acceptable N-oxide;    -   (e) optionally converting an N-oxide form of a compound of the        invention to its unoxidized form;    -   (f) optionally resolving an individual isomer of a compound of        the invention from a mixture of isomers;    -   (g) optionally converting a non-derivatized compound of the        invention into a pharmaceutically acceptable prodrug derivative;        and    -   (h) optionally converting a prodrug derivative of a compound of        the invention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

EXAMPLES

The following examples and intermediates serve to illustrate theinvention without limiting the scope thereof. Some abbreviations used inthe examples are as follows: acetic acid (AcOH); triethylamine (TEA);tetrahydrofuran (THF); aqueous (aq.); atmosphere (atm.);2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (BINAP);4-dimethylaminopyridine (DMAP); tert-butoxycarbonyl (Boc);1,1-carbonyldiimidazole (CDI); di-tert-butyl dicarbonate (BOC₂O);benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP); dichloromethane (DCM); diethyl ether (Et₂O);p-toluene sulfonic acid (PTSA); ethyl acetate (EtOAc); ethanol (EtOH);lithium bis(trimethylsilyl)amide (LHMDS); diisopropyl azodicarboxylate(DIAD); N,N-diisopropyl-ethylamine (DIEA or DIPEA);N,N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO);diphenylphosphoryl azide (DPPA); hour(s) (h);2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU); High Performance Liquid Chromatography(HPLC); lithium aluminium hydride (LAH); liquid chromatography coupledwith mass spectrometry (LCMS); lithium diisopropylamide (LDA); methanol(MeOH); milliliter(s) (mL); minute(s) (min); microwave (MW);n-butyllithium (n-BuLi);1,1-bis(diphenylphosphino)-ferrocenedichloropalladium (II)(PdCl₂(dppf)); tris(dibenzylideneacetone)dipalladium (0) (Pd₂(dba)₃);dichlorobis(triphenylphosphine)palladium (II) (PdCl₂(PPh₃)₂); roomtemperature (RT); trifluoroacetic acid (TFA); tetrahydrofuran (THF);thin layer chromatography (TLC); retention time (t_(R)); &4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantophos).

LCMS data for the compounds below were generated on a Synergi 2.5uMAX-RP 100A Mercury column with the mobile phase: A=0.1% Formic acid,B=ACN, applying a gradient: 0/30, 0.5/30, 1.5/95, 2.4/95, 3.0/30 at aflow of 2.0 ml/min and a temperature of 30.0° C. Five different HPLCmethods were used and the method used is given for each individualcompound in Table 1 below. Unless mentioned otherwise, the method usedfor the detailed examples is Method-1. Conditions were as follows:

Method-1 Information:

-   -   Column: Zorbax XDB C18 5u 4.6×150 mm    -   Mobile Phase: A=0.01% TFA in Water, B=MeOH:ACN (1:1)    -   Gradient Time % B: 0/30, 1/70, 6/100, 8/100, 10/30, 12/30    -   Flow: 1.0 ml/min.    -   Temperature: 40.0° C.

Method-2 Information:

-   -   Column. AG/C18/15-010    -   Mobile Phase: A=Water, B=ACN (1:1)    -   Gradient: 70/30    -   Flow: 1.0 ml/min.    -   Temperature: 40.0° C.

Method-3 Information:

-   -   Column. Kienetex 5u C18 100A 150×4.60 mm    -   Mobile Phase: A=0.01% TFA in Water, B=MeOH:ACN (1:1)    -   Gradient Time % B: 0/5, 1/5, 6/100, 8/100, 10/5, 12/5    -   Flow: 1.0 ml/min.    -   Temperature: 40.0° C.

Method-4 Information:

-   -   Column: Zorbax Eclipse Plus C18 RR HD 2.1-100 mm 18u    -   Mobile Phase: A=0.01% TFA in Water, B=MeOH:ACN (1:1)    -   Gradient Time % B: 0/10, 5/30, 1.5/100, 3/100, 4/10, 5/30    -   Flow: 0.5 ml/min.    -   Temperature: 40.0° C.

Method-5 Information:

-   -   Column. Kienetex 2.6u C18    -   Mobile Phase: A=0.01% TFA in Water, B=MeOH:ACN (1:1)    -   Gradient Time % B: 0/10, 0.5/30, 1.5/100, 3/100, 4/10, 5/10    -   Flow: 1.4 ml/min.    -   Temperature: 40.0° C.

Intermediate 1.1 5-bromo-4-fluoro-2-((2-nitrovinyl)amino)benzoic acid

Step 1.1: Synthesis of intermediate 1.1;5-bromo-4-fluoro-2-((2-nitrovinyl)amino)benzoic acid

Part-a: HCl gas is purged through a solution of2-amino-5-bromo-4-fluorobenzoic acid (38 g, 0.162 mol) in 570 ml of1,4-dioxane for 1.5-2 hrs at 0° C. The mixture was stirred for 2 hrs andallowed to stand overnight at RT. The solid was filtered, washed withdiethyl ether and dried under vacuum to afford an HCl salt (44.5 g) of2-amino-5-bromo-4-fluorobenzoic acid.

Part-b: To a stirred solution of NaOH (22 g, 0.162 mol) in water (44ml), cooled to 0-5° C., nitromethane (2×8.5 ml) was added drop wise soas to maintain an internal temperature of 25-30° C. After the additionwas complete, the cooling bath was removed, causing a spontaneous risein temperature to 70° C., and a red coloration to develop. The mixturewas then cooled to 25-30° C. The resulting orange red solution wascarefully poured on to ice (48 g) and conc. HCl (48 ml) to afford themethazonic acid.

Part-c: To a suspension of HCl salt (44 g) of2-amino-5-bromo-4-fluorobenzoic (Part-a solid) in Con. HCl (140 ml) andwater (800 ml) was added methazonic acid (Part-b). The resulting mixturewas stirred for 30 mins. The solid that precipitated out was allowed tostand overnight before filtering, washing with excess of water andmethanol (60 ml) and drying under vacuum for 3-4 hrs to afford the5-bromo-4-fluoro-2-((2-nitrovinyl)amino)benzoic acid 44 g, 88.5% ofyield. ¹H NMR (DMSO-d₆, 300 MHz): δ 13.0 (d, 1H), 8.20 (d, 1H), 8.0 (m,1H), 7.95 (d, 1H), 6.90 (d, 1H); LCMS: 77.7%, m/z=304.9 (M+1).

Intermediate 1.2 6-bromo-7-fluoro-3-nitroauinolin-4-ol

Step 1.2: Synthesis of intermediate-1.2;6-bromo-7-fluoro-3-nitroquinolin-4-ol:5-bromo-4-fluoro-2-((2-nitrovinyl)amino)benzoic acid (44 g, 0.144 mol)was heated in acetic anhydride, (220 ml) at 110° C. until dissolutionwas accomplished, and cooled to 40° C. Potassium acetate was (16.9 g)was added and the resulting mixture was heated to 140° C. for 45 min.The reaction mixture was cooled to RT. The resulting solid was filteredand washed with acetic acid (25 ml), water, methanol (30 ml) and driedunder vacuum to afford the 6-bromo-7-fluoro-3-nitroquinolin-4-ol 18 g,43.4% of yield. ¹H NMR (DMSO-d₆, 300 MHz): δ 13.1 (bs, 1H), 9.25 (s,1H), 8.41 (d, 1H), 7.61 (d, 1H); LCMS: 98.2%, m/z=286.9 (M+1).

Intermediate 1.3 6-bromo-4-chloro-7-fluoro-3-nitroquinoline

Step 1.3: Synthesis of intermediate-1.3;6-bromo-4-chloro-7-fluoro-3-nitroquinoline:6-bromo-7-fluoro-3-nitroquinolin-4-ol (20 g, 0.069 mol) was refluxed inPOCl₃ (180 ml) and TEA (11.8 ml, 0.083 mol) for 24 h at 120° C. Thereaction mixture was cooled to RT poured slowly into ice-water. Theprecipitated solid was filtered and washed with ice-cold water. Thesolid was dissolved in dichloromethane and washed with cold-brinesolution. The organic layer was dried over sodium sulphate andevaporated under vacuum. The residue was purified by columnchromatography on silica gel (10% EtOAc-Hexane) to afford6-bromo-4-chloro-7-fluoro-3-nitroquinoline (19 g; 89.6% yield). ¹H NMR(DMSO-d₆, 300 MHz): δ 9.4 (s, 1H), 8.76 (d, 1H), 8.22 (d, 1H); LCMS:96.5%, m/z=304.9 (M+1).

Intermediate 1.4

Step-1 on Scheme 1 hereinabove: General rocedure for synthesis ofintermediate 1.4:

Method-A: 6-bromo-4-chloro-7-fluoro-3-nitroquinoline (1 mmol) anddesired aryl amine, 1 mmol) were stirred in AcOH for 2-3 hrs at RT.After completion of the reaction TLC (20% EtOAc-Hexane), the reactionmixture was diluted with water. The resultant yellow precipitate wasfiltered and washed with water. The solid was dissolved in EtOAc-THF(1:1) and washed with saturated NaHCO₃ solution. The organic layer wasdried over Na₂SO₄ and evaporated to afford intermediate 1.4. The crudematerial was purified by column chromatography.

Method-B: 6-bromo-4-chloro-7-fluoro-3-nitroquinoline (1 mmol) anddesired alkyl amines (1 mmol) are dissolved in DMF and added DIPEA atRT. The reaction mass is stirred at RT for 3-4 hrs. The reaction wasmonitored by TLC (20% EtOAc-Hexane). After completion, water was addedto the reaction and the resultant yellow precipitate is filtered-off,washed with water and dried under vacuum for 1-2 hrs to affordIntermediate 1.4.

Intermediate 1.5 Step-2 on Scheme 1 hereinabove: General procedure forsynthesis of intermediate 1.5

Method C: Intermediate 1.4 obtained from either method A or B wasreduced with Raney-Ni under H₂ gas pressure (balloon) in a solventmixture MeOH:THF (2:1) for 5-6 hrs. After completion of the reaction byTLC (60% EtOAc-Hexane), the reaction mass was filtered through a celitebed and washed with ethyl acetate. The filtrate was evaporated todryness to give interemedaited 1.5.

Method D: Intermediate 1.4 (1 mol) obtained from either method A or Bwas treated with sodium dithionate (5 mol) in dioxane for 1-6 hrs. Aftercompletion of the reaction by TLC (60% EtOAc-Hexane), the reactionmixture was partitioned between EtOAc and water. The separated organiclayer was washed with water, brine, dried over Na₂SO₄ and evaporated todryness to get desired intermediate 1.5.

Intermediate 1.6

Step-3 on Scheme 1 hereinabove, General procedure for synthesis ofintermediate 1.6:

Intermediate 1.5 obtained in step 1.5 was heated in triethylorthoformate for 4 hrs at 105° C. After completion of the reaction byTLC (60% EtOAc-Hexane), the solvent was evaporated completely underreduced pressure and the residue was purified by column chromatographyon silica gel (MeOH/DCM) to give interemediate 1.6.

Intermediate 1.7

Step-4 on Scheme 1 hereinabove: General procedure for synthesis ofintermediate 1.7: To a stirred solution of intermediate 1.6 in a mixtureof toluene:ethanol (8:2) in a seal tube, was added Pd(PPh₃)₄ (0.05 eq).The reaction mixture was purged with Organ gas for 10 mins before addingaryl/heteroaryl boronic acids/esters and 2M Na₂CO₃ solution (2 eq). TheOrgan gas purging was continued for an additional 15 mins before sealingthe reaction vial. The reaction mass was heated at 95° C. for 4-16 hrs.The reaction was monitored by TLC (100% EtOAc). After completion of thereaction, the reaction mass was partitioned between EtOAc and water. Theorganic layers were separated, washed with water and brine, dried overNa₂SO₄ and evaporated under vacuum. The crude residue was purified bycolumn chromatography on silica gel (MeOH/DCM) to give intermediate 1.7.

Example 1A1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone

Step-1, Synthesis of (3S,4S)-tert-butyl4-((6-bromo-7-fluoro-3-nitroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate,1

6-Bromo-4-chloro-7-fluoro-3-nitroquinoline (17.5 g, 0.0057 mol) wastaken in dry DMF (200 mL) under N₂ atmosphere. DIPEA (14.8 g, 0.114 mol)and (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (12.5 g,0.057 mol) in dry DMF (50 mL) was added sequentially at RT. Theresulting mixture was stirred for overnight at RT. The reaction wasmonitored by TLC (30% EtOAc/Hexane), after completion of reaction, thereaction mixture poured into ice water and extracted with EtOAc (3×200mL). The combined EtOAc layers were washed with brine solution andwater, dried over sodium sulphate. The organic layer was evaporatedunder vacuum and the residue was purified by column chromatography onsilica gel (10-50% EtOAc-Hexane) to afford the (3S,4S)-tert-butyl4-((6-bromo-7-fluoro-3-nitroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate,1 (27 g, 956% yield). ¹HNMR (CDCl₃, 400 MHz): δ 9.37 (s, 1H) 8.83-8.81(d, 1H) 8.48-8.46 (d, 1H) 7.74-7.71 (d, 1H), 4-58-4.40 (m, 2H),4.19-4.12 (m, 2H), 2.95-2.87 (m, 2H) 2.27-2.23 (m, 1H) 1.79-1.66 (m,1H), 1.47 (s, 9H); LCMS: 98.84%, (M+2) 488.7; HPLC: 99.47%.

Step-2, Synthesis of (3S,4S)-tert-butyl4-((3-amino-6-bromo-7-fluoroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate,2

(3S,4S)-tert-butyl4-((6-bromo-7-fluoro-3-nitroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate(27 g, 0.055 mol) was taken in 1,4-dioxane (150 mL). Solution of sodiumdithionite (29 g, 0.166 mol in 150 mL water) was added at RT and theresulting mixture was stirred for 5 h at RT. The reaction was monitoredby TLC (50% EtOAc/hexane), after completion of reaction the reactionmixture was poured into ice water and extracted with EtOAc (3×200 mL).The combined organic layers were washed with brine and water, dried oversodium sulphate. The organic layer was evaporated under vacuum, toafford the (3S,4S)-tert-butyl4-((3-amino-6-bromo-7-fluoroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate,2 (27 g). This material used directly in next step without purification.LCMS: 99.5%, m/z=456.7 (M⁺).

Step-3, Synthesis of (3S,4S)-tert-butyl4-(8-bromo-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxylate,3

(3S,4S)-tert-butyl4-((3-amino-6-bromo-7-fluoroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylate(27 g, 0.059 mol) was heated in triethylorthoacetate (150 mL) under N₂atmosphere for 5 h at 120° C. The reaction was monitored by TLC (5%MeOH/DCM). The volatiles were concentrated under vacuum, the obtainedcrude product was purified by column chromatography on silica gel (0-3%MeOH/DCM) to afford (3S,4S)-tert-butyl4-(8-bromo-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxylate(15 g, yield from two steps). ¹HNMR (CDCl₃, 400 MHz): δ 9.28-9.23 (d,1H), 8.43-8.34 (dd, 1H), 8.01-7.99 (d, 1H), 5.60-5.35 (m, 1H), 5.25-4.85(m, 1H), 4.75-4.35 (m, 2H), 3.15-2.95 (m, 2H), 2.79 (s, 3H), 2.40-2.05(m, 2H), 1.57 (s, 9H); LCMS: 100%, m/z=480.8 (M⁺); HPLC: 97.31%.

Step-4, Synthesis of (3S,4S)-tert-butyl4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxylate,4

tert-Butyl4-(8-bromo-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxylate(9 g, 0.018 mol) was dissolved in toluene:ethanol (8:2, 50 ml) in a 250ml seal tube and degasified the reaction mixture with argon gas for 15minutes. Tetrakis (2.1 g, 0.0018 mol) was added and degasified thereaction mixture with argon gas for 5 minutes,2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine(8 g, 0.024 .mol), followed by 2M Na₂CO₃(5 ml) was added and finallydegasified the reaction mixture with argon gas for 10 minutes. Theresulting reaction mixture was heated 5 h at 90° C. The reaction wasmonitored by TLC (5% MeOH/DCM), after completion of reaction by TLC thereaction mixture poured into ice water and extracted with EtOAc (3×100mL). The combined organic layers were washed water, brine solution,dried over sodium sulphate and evaporated under vacuum. The residue waspurified by column chromatography on silica gel (0-3% MeOH/DCM) toafford (3S,4S)-tert-butyl4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxylate,4 (10.2 g, 95% yield). ¹HNMR (CDCl₃, 400 MHz): δ 9.28 (d, 1H), 8.68-8.60(m, 2H), 8.34-8.31 (d, 0.8H), 8.17 (d, 0.2H), 8.09-8.02 (m, 1H),7.58-7.44 (m, 2H), 7.30 (dd, 1H), 7.16-7.10 (m, 1H), 5.62-5.04 (m, 1H),4.89-4.25 (m, 3H), 3.10-2.75 (m, 5H), 2.40-2.20 (m, 2H), 1.51 (s, 9H);LCMS: 98.99%, m/z=607.45 (M+1); HPLC: 96.89%, rt: 4.32 min.

Step-5, Synthesis of8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-((3S,4S)-3-fluoropiperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinolineTFA salt, 5

TFA (20 ml) was added drop wise to a solution of(3S,4S)-tert-butyl-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxylate(10 g, 0.0164 mol) in dry DCM (150 mL) at 0° C. under N2 atmosphere.After addition completed, the reaction mixture allowed to RT and stirredfor 3 h. The reaction was monitored by TLC (5% MeOH/DCM), aftercompletion of reaction by TLC, the volatiles were concentrated undervacuum. The obtained residue was triturated with diethyl ether. Thesolid was filtered and dried under vacuum to afford TFA salt of8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-((3S,4S)-3-fluoropiperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinoline(11 g, quantitative). LCMS: 99.41%, m/z=507.1 (M+1) (Free base); HPLC:96.43%, 6.002 min.

Step-6, Synthesis of2-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-oxoethylacetate, 6

HOBT (5.4 .g, 0.040 mol) and EDCI.HCl (7.64 g, 0.040 mol) wassequentially added to a solution of 2-acetoxyacetic acid (4.3 .g, 0.036mol) in dry DMF (100 mL) under N₂ atmosphere at 0° C. The resultingmixture was stirred at RT for 30 min. A solution of8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-((3S,4S)-3-fluoropiperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinoline.TFA salt (11.0 g, 0.0178 mol) in dry DMF (50 ml) and TEA (5.4 g, 0.053mol) was added to the reaction mixture. The resulting reaction mixturewas allowed to RT and stirred for 3 h. The reaction was monitored by TLC(5% MeOH/DCM). After completion of reaction, the reaction mixture waspoured into saturated ice cold NaHCO₃ solution and extracted with EtOAc(3×200 mL). The combined EtOAc layers were washed with brine solutionand water, dried over sodium sulphate and evaporated under vacuum. Theresidue was purified by column chromatography on silica gel (0-3%MeOH/DCM) to afford the2-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-oxoethylacetate, 6 (8 g, 85% yield). ¹HNMR (CDCl₃, 400 MHz): δ 9.31 (d, 1H),8.68-8.60 (m, 2H), 8.34 (d, 0.5H), 8.12-8.01 (m, 1.5H), 7.59 (d, 0.5H),7.54-7.45 (m, 1.5H), 7.37-7.30 (m, 1H), 7.18-7.11 (m, 1H), 5.69-5.16 (m,2H), 4.99-4.61 (m, 3H), 4.37-4.25 (m, 0.5H), 4.01-3.88 (m, 0.5H), 3.50(d, 1H), 3.03-2.90 (m, 2H), 2.88 (s, 1.5H), 2.81 (s, 1.5H), 2.50-2.33(m, 1H), 2.22 (s, 1.5H), 2.07 (s, 1.5H); LCMS: 98.99%, m/z=607.45 (M+1);HPLC: 96.89%, rt: 4.32 min.

Step-7, Synthesis of1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone

NaHCO₃ (11 g, 0.1309 mol) was added to a stirred solution of2-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-oxoethylacetate(8 g, 0.013 mol) in MeOH (300 mL) at RT and stirred for 24 h. Thereaction was monitored by TLC (5% MeOH/DCM), after completion ofreaction, the reaction mixture was filtered and wand washed with MeOH(100 mL). The filtrate was concentrated to remove methanol and theresidue was dissolved in DCM (200 mL) and washed with water, brinesolution, dried over sodium sulphate and evaporated under vacuum. Theresidue was purified by column chromatography on silica gel (0-4%MeOH/DCM) to afford the1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone(6.0 g, 81% yield). Obtained solid was recrystallized in EtOH(alternatively in MeOH) ¹HNMR (CDCl₃, 400 MHz): δ 9.33 (s, 1H),8.65-8.64 (d, 2H), 8.08-8.05 (d, 1H), 8.00-7.85 (m, 1H), 7.51-7.30 (m,2H), 7.30-7.28 (dd, 1H), 7.15-7.13 (m, 1H), 5.65-5.25 (m, 1H), 4.96-4.75(m, 1H), 4.35-4.15 (m, 2H), 3.92-3.74 (m, 2H), 3.35-3.15 (m, 1H),3.05-2.85 (m, 2H), 2.80 (s, 3H), 2.45-2.15 (m, 2H); LCMS: 100%,m/z=565.1 (M+1); HPLC (Method-3): 99.80%, Chiral HPLC: 99.48%, rt=20.38min., Column. AG/CHIRALPAK AD-H/03.

Free Form

A free form of1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanonein crystalline form (Form A of the free form) was produced from coolingcrystallization of a supersaturated solution of the compound in ethanolat concentrations of about 110 mg/ml. 17.6 g of compound 1A was heatedin 500 ml of ethanol under nitrogen atmosphere to reflux temperature.Approx. 1100 mL ethanol was added drop wise at reflux temperature, untilthe entire solid dissolved and a clear solution was obtained. The clearsolution was cooled to room temperature and kept under slow stirring for48 h. The precipitated solid was filtered and washed with ethanol. Wt:16.1 g, HPLC: 99.20%, ¹HNMR shown residual ethanol was trapped. Theobtained crystalline solid of Ex. 1A (16 g) was heated to reflux with200 mL of HPLC grade toluene (compound not soluble in toluene) for 2 h.Then the reaction mixture was slowly cooled to room temperature, thesolid was filtered and washed with toluene and dried under vacuum. Wt:15.1 g, HPLC: 99.80%, LCMS: 99.39%, ¹HNMR was clean and showed noresidual EtOH peaks. The XRPD pattern of a sample prepared according tosuch a method is shown in FIG. 1. Measurements were performed performedat a temperature of about 22° C. and an x-ray wavelength, λ, of 1.54006Å. (CuKα 1.54006 Å.). The following xray method was used:

Instrument Bruker D8 advantage Geometry Reflection Detector VantecGenerator parameter 30 kV; 40 mA San range 2-40° 2-Theta San rate 107.1s Step size 0.0170 Slits (from left to right) U12

Summary of XRPD Pattern

Degrees 2-Theta (±0.1) Relative Intensity 7.324 Medium 9.758 Low 11.285Low 12.165 Low 18.073 Medium 18.845 High 19.569 Medium 21.219 Medium22.564 MediumIn one embodiment, Form A of the free form of1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanonein crystalline form is characterized by an XRPD pattern with at leastfour, more preferably five, most preferably all of the following peaksat an angle of refraction 2 theta (20) of 7.3, 18.1, 18.8, 19.6, 21.2and 22.6, ±0.1, respectively.

In one embodiment, Form A of the free form of1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanonein crystalline form is characterized by an XRPD pattern substantiallythe same as the XRPD pattern shown in FIG. 1.

The melting point of Form A of the free from was determined by heatingat 10° C./minute to be about 238° C.

The following are further embodiments of the invention:

Embodiment 1a

A free form of1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanonein solid form.

Embodiment 2a

The free form according to embodiment 1a, wherein the free form is incrystalline form.

Embodiment 3a

The free form according to embodiment 2a, wherein the free form ischaracterized by an XRPD pattern substantially the same as the XRPDpattern shown in FIG. 1.

Embodiment 4a

The free form according to embodiments 2a or 3a, wherein the free formis in substantially pure form.

Embodiment 5a

The free form according to embodiments 2a or 3a, wherein the free formhas a purity greater than 90 weight %.

Example 28-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-(1-(2-methoxyethyl)piperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinoline

To a stirred solution of7-fluoro-8-(2-fluoro-4-(pyrimidin-2-yloxy)phenyl)-2-methyl-1-(piperidin-4-yl)-1H-imidazo[4,5-c]quinolone.TFA salt (0.2 g, 0.408 mmol) in dry DMF (2 ml) at 0° C., was added DIPEA(0.2 mL, 1.2 mmol) followed by 1-bromo-2-methoxyethane (0.08 g, 0.61mmol). The reaction mixture was stirred at room temperature for 48 h andmonitored by TLC (10% MeOH in DCM). The reaction mixture was poured intoice water, extracted with ethyl acetate (3×25 mL). The combined organiclayers were washed with ice-cold water, brine solution, dried overNa₂SO₄ and concentrated purified by silica-gel chromatography using 2%MeOH in DCM as eluent to afford8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-(1-(2-methoxyethyl)piperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinoline,(0.1 g, 46%). ¹H NMR (DMSO-d₆, 400 MHz): δ 9.21 (s, 1H), 8.73 (d, 2H),8.42-8.35 (m, 1H), 8.07 (d, 1H), 7.73 (d, 1H), 7.67 (d, 1H), 7.43 (dd,1H), 7.37 (t, 1H), 4.85-4.65 (m, 1H), 3.16 (s, 3H), 3.15-3.02 (m, 3H),2.77 (s, 3H), 2.68 (t, 2H), 2.34 (t, 2H), 2.32-2.22 (m, 3H), 2.10-1.95(m, 2H); LCMS: 90.41%, m/z=547.10 (M+1); HPLC: 96.15%, rt: 3.01 min.

Example 58-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]quinoline

To a stirred solution of7-fluoro-8-(2-fluoro-4-(pyrimidin-2-yloxy)phenyl)-2-methyl-1-(piperidin-4-yl)-1H-imidazo[4,5-c]quinolone.TFA salt (0.05 g, 0.102 mmol) in dry DCM (2 ml) at 0° C., was addedDIPEA (0.2 mL) followed by methanesulfonyl chloride (0.1 mL). Thereaction mixture was stirred at room temperature for 4 h and monitoredby TLC (5% MeOH in DCM). The reaction mixture was poured into ice water,extracted with ethyl acetate (3×15 mL). The combined organic layers werewashed with ice-cold water, brine solution, dried over Na₂SO₄ andconcentrated purified by silica-gel chromatography using 2% MeOH in DCMas eluent to afford8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]quinoline(0.025 g, 46%). ¹H NMR (DMSO-d₆, 400 MHz): δ 9.20 (s, 1H), 8.71 (d, 2H),8.55-8.47 (m, 1H), 8.06 (d, 1H), 7.74 (d, 1H), 7.61 (s, 1H), 7.41-7.32(m, 2H), 5.45-5.33 (m, 1H), 3.85-3.77 (m, 2H), 3.09-2.92 (m, 2H), 2.89(s, 3H), 2.79 (s, 3H), 2.35-2.17 (m, 4H); LCMS: 98.33%, m/z=567.4 (M+1);HPLC: 94.22%, rt: 6.80 min.

Example 31 Synthesis of4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide

To a stirred solution of8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1-(piperidin-4-yl)-1H-imidazo[4,5-c]quinolone.TFA salt (0.25 g, 0.491 mmol) in dry DCM (5 ml) at 0° C., was added TEA(0.276 mL, 1.964 mmol) followed by trimethylsilyl isocyaante (0.085 mL,0.744 mmol). The reaction mixture was stirred at room temperature for 4h and monitored by TLC (10% MeOH in DCM). The reaction mixture waspoured into ice water, extracted with ethyl acetate (3×15 mL). Thecombined organic layers were washed with ice-cold water, brine solution,dried over Na₂SO₄ and concentrated purified by silica-gel chromatographyusing 8% MeOH in DCM as eluent to afford4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide(0.08 g, 16%). ¹HNMR (DMSO-d₆, 400 MHz): δ 9.19 (s, 1H), 8.51 (d, 1H),8.40 (m, 1H), 8.05 (d, 1H), 7.72-7.54 (m, 2H), 7.42-7.36 (m, 1H), 7.22(d, 1H), 6.10-5.50 (m, 3H), 5.10-4.80 (m, 1H), 4.20 (m, 2H), 2.92 (t,2H), 2.77 (s, 3H), 2.46 (s, 3H), 2.10-1.90 (m, 3H); LCMS: 99.6%,m/z=546.5 (M+1); HPLC: 96.6%, rt: 6.26 min.

By repeating the procedures described in the above examples, usingappropriate starting materials, the following compounds of Formula I, asidentified by their chemical name in Table 1.1, are obtained. Examples55 and 56 can be prepared in analoguous manner from the commercialbuilding blocks 4-aminotetrahydro-2H-thiopyran 1,1-dioxide (CAS210240-20-3) and 3-fluorotetrahydro-2H-pyran-4-amine (CAS 1416371-97-5).

TABLE 1.1 Ex. Steps Chemical name  1A Step1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone 1B Step1-((3R,4R)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone 2 Step 8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-(1-(2- 1-5,8 methoxyethyl)piperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinoline  3Step2-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 8 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)ethanol  4 Step8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1-(1-((3-1-5, 8methyloxetan-3-yl)methyl)piperidin-4-yl)-1H-imidazo[4,5-c]quinoline  5Step 8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1-(1-1-5, 10 (methylsulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]quinoline  6Step1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one 7 Step1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 8 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)propan-2-ol  8 Step8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-1-(1-(cyclopropylsulfonyl)piperidin-4-1-5, 10 yl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinoline  9 Step8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-(1- 1-5, 10(isopropylsulfonyl)piperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinoline10 Step4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-1-5, 10 c]quinolin-1-yl)-N,N-dimethylpiperidine-1-sulfonamide 11 Step4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-1-5, 6 c]quinolin-1-yl)-N,N-dimethylpiperidine-1-carboxamide 12 Step1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)ethanone 13 Step2-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 8 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)acetamide 14 Step1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone 15Step2-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-1H-1-5, 8 imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)ethanol 16Step2-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 8 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)propan-1-ol 17 Step2-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-1-5, 8 c]quinolin-1-yl)-4-methylpiperidin-1-yl)ethanol 18 Step2-(4-(7-fluoro-8-(2-methoxy-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-1-5, 8 imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)ethanol 19Step2-(4-(7-fluoro-8-(2-methoxy-4-(pyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-1-5, 8 c]quinolin-1-yl)-4-methylpiperidin-1-yl)ethanol 20 Step1-(4-(7-fluoro-8-(2-methoxy-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-1-5, 6imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxypropan-1-one21 Step1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-1H-1-5, 6imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxypropan-1-one22 Step1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 8 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-3-hydroxy-2-(hydroxymethyl)propan-1-one 23 Step2-((4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 8imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)methyl)propane-1,3-diol 24Step1-(4-(7-fluoro-8-(2-methoxy-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-1-5, 6imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxyethanone25 Step8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1-(1-(oxetan-3-1-5, 8 ylmethyl)piperidin-4-yl)-1H-imidazo[4,5-c]quinoline 26 Step1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-1H-1-5, 6imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxyethanone27 Step1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-1-5, 6 c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxypropan-1-one 28Step1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone 29Step1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one30 Step4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-1-5, 6 c]quinolin-1-yl)piperidine-1-carboxamide 31 Step4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide 32 Step8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1-(1-1-5, 10 (methylsulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]quinoline 33Step1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-1-5, 6 c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxyethanone 34Step(S)-1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one35 Step(S)-1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-1-5, 6methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one36 Step2-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 8 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)ethanol 37 Step4-(7-fluoro-8-(2-methoxy-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H- 1-5,6 imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidine-1-carboxamide 38 Step4-(7-fluoro-8-(2-methoxy-4-(pyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-1-5, 6 c]quinolin-1-yl)-4-methylpiperidine-1-carboxamide 39 Step2-amino-1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)ethanone 40 Step2-amino-1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-1-5, 6 methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)ethanone 41Step1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)-4-(hydroxymethyl)piperidin-1-yl)-2-hydroxyethanone 42 Step1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-methoxyethanone 43AStep (R orS)-1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-fluoropropan-1-one(Peak 1) 43B Step (R orS)-1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-fluoropropan-1-one(Peak 2) 44 Step1-(4-(8-(2-chloro-4-((6-(hydroxymethyl)pyridin-2-yl)oxy)phenyl)-7-fluoro-2-1-5, 6methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone45 Step4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-1-5, 6 c]quinolin-1-yl)-N-(2,2,2-trifluoroethyl)piperidine-1-carboxamide46 Step1-(4-(8-(2-chloro-4-((4-fluoropyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone 47Step1-(4-(8-(2-chloro-4-((6-fluoropyridin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone 48Step1-(4-(8-(2-chloro-4-((5-fluoro-4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-1-5, 6methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone49 Step2-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-oxoethylacetate 50 Step8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-((3S,4S)-3-fluoro-1-1-5, 10(methylsulfonyl)piperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinoline 51Step1-((3S,4S)-4-(8-(2-chloro-4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)-7-1-5, 6fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone 52 Step1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-methoxyethanone53 Step1-((3S,4S)-4-(8-(2-chloro-4-((5-fluoro-4-methylpyrimidin-2-yl)oxy)phenyl)-7-1-5, 6fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone 54 Step1-(4-(8-(2-chloro-4-((4-cyclopropylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-1-5, 6methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone55 NA4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide 56 NA8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-(3-fluorotetrahydro-2H-pyran-4-yl)-2-methyl-1H-imidazo[4,5-c]quinoline 57 Step2-((3R,4R)-4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-1-5, 8methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)acetonitrile58 Step2-((3S,4S)-4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-1-5, 8methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)acetonitrile59 Step4-(3-chloro-4-(1-(1-(cyanomethyl)piperidin-4-yl)-7-fluoro-2-methyl-1H-1-5, 8imidazo[4,5-c]quinolin-8-yl)phenoxy)-6-methylpyrimidine-2-carbonitrile60 Step2-(4-(8-(2-chloro-4-((1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)oxy)phenyl)-7-1-5, 8fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)acetonitrile61 Step2-((3R,4R)-3-fluoro-4-(7-fluoro-8-(2-methoxy-4-(pyrimidin-2-yloxy)phenyl)-2-1-5, 8 methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)acetonitrile62 Step2-((3S,4S)-3-fluoro-4-(7-fluoro-8-(2-methoxy-4-(pyrimidin-2-yloxy)phenyl)-2-1-5, 8 methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)acetonitrile63 Step3-(3-chloro-4-(7-fluoro-1-(1-(2-hydroxyacetyl)piperidin-4-yl)-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-8-yl)phenoxy)-1-methylpyridin-2(1H)-one 64Step4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-1-5, 6 c]quinolin-1-yl)-4-methylpiperidine-1-carboxamide 65 Step4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-1H- 1-5,6 imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidine-1-carboxamide 66 Step1-(4-(8-(2-chloro-4-((4-methoxy-6-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-1-5, 61H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxyethanone67 Step1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-methoxyethanone 68Step1-((3S,4S)-4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-1-5, 6 methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone 69 Step6-(3-chloro-4-(7-fluoro-1-(1-(2-hydroxyacetyl)-4-methylpiperidin-4-yl)-1H-1-5, 6 imidazo[4,5-c]quinolin-8-yl)phenoxy)-3-methylpyrimidin-4(3H)-one70 Step4-(7-fluoro-8-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide 71 Step1-(4-(7-fluoro-8-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone 72Step6-(3-chloro-4-(7-fluoro-1-(1-(2-hydroxyacetyl)piperidin-4-yl)-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-8-yl)phenoxy)-3-methylpyrimidin-4(3H)-one73 Step4-(8-(2-chloro-4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)phenyl)-7-1-5, 6fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide74 Step4-(8-(2-chloro-4-((1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)oxy)phenyl)-7-1-5, 6fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide75 Step4-(8-(2-chloro-4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)phenyl)-7-1-5, 6fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidine-1-carboxamide76 Step4-(7-fluoro-2-methyl-8-(2-methyl-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide 77 Step1-(4-(7-fluoro-2-methyl-8-(2-methyl-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1-5, 6 1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone78 Step1-(4-(7-fluoro-2-methyl-8-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone 79Step4-(7-fluoro-8-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-imidazo[4,5-1-5, 6 c]quinolin-1-yl)-4-methylpiperidine-1-carboxamide 80 Step4-(7-fluoro-8-(2-fluoro-4-(pyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-5, 6 1-yl)-4-methylpiperidine-1-carboxamide 81 Step(S)-3-(3-chloro-4-(7-fluoro-1-(1-(2-hydroxypropanoyl)piperidin-4-yl)-2-methyl-1-5, 6 1H-imidazo[4,5-c]quinolin-8-yl)phenoxy)-1-methylpyridin-2(1H)-one82 Step4-(8-(2-chloro-4-((4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)oxy)phenyl)-7-1-5, 6fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide83 Step1-(4-(7-fluoro-8-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-1-5, 6imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxyethanone84 Step2-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 8 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)acetonitrile 85 Step2-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 8 imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)acetonitrile86 Step((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)(oxetan-2-yl)methanone87 Step1-((3S,4S)-4-(8-(2-chloro-4-((5-fluoro-4-methylpyrimidin-2-yl)oxy)phenyl)-7-1-5, 6fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone 88 Step1-((3S,4S)-3-fluoro-4-(7-fluoro-8-(2-methoxy-4-(pyrimidin-2-yloxy)phenyl)-2-1-5, 6methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone89 Step1-((3S,4S)-4-(8-(2-chloro-4-((4-(hydroxymethyl)pyrimidin-2-yl)oxy)phenyl)-7-1-5, 6fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone 90 Step1-((3S,4S)-3-fluoro-4-(7-fluoro-2-methyl-8-(2-methyl-4-(pyrimidin-2-1-5, 6 yloxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone 91 Step2-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-oxoethylhydrogen sulfate 92 Step1-((3S,4S)-3-fluoro-4-(7-fluoro-8-(2-fluoro-4-(pyrimidin-2-yloxy)phenyl)-2-1-5, 6methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone93 Step1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)ethanone 94Step(3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxamide 95Step(S)-1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1-5, 61H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxypropan-1-one96 Step1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6 imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-fluoroethanone 97Step1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-fluoroethanone 98Step1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-1-5, 6imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-3-hydroxypropan-1-one99 Step1-((3S,4S)-4-(8-(2-chloro-4-((4-methoxy-1,3,5-triazin-2-yl)oxy)phenyl)-7-1-5, 6fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone

Intermediate 1.8

Step-2.1: Synthesis of tert-butyl4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate, 2.2

Tert-butyl 4-oxopiperidine-1-carboxylate, 1.1 (250 g, 1.256 mol) wastaken in dry DMF (150 mL) under N₂ atmosphere and added TEA (230 g, 2.27mmol) at room temperature. The reaction mixture was cooled to 0° C.,added trimethylsilyl chloride (178 g, 1.64 mol) drop wise for 30minutes. After addition completed the reaction mixture heated at 80° C.for 16 h. The reaction was monitored by TLC (20% EtOAc/hexane), andallowed to cool the reaction mixture to room temperature, poured intoice water and extracted with EtOAc (3×200 mL). The combined organiclayers were washed with water, brine solution, dried over Na₂SO₄ andevaporated under vacuum. The residue was purified by columnchromatography on silica gel (5-10% EtOAc-Hexane) to afford tert-butyl4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate, 2.2 (300g, 87.79%). ¹HNMR (CDCl₃, 400 MHz): δ 4.78 (s, 1H), 3.87-3.80 (m, 2H),3.55 (t, 2H), 2.15-2.05 (m, 2H), 1.45 (s, 9H), 0.19 (s, 9H).

Step-2.2: Synthesis of tert-butyl3-fluoro-4-oxopiperidine-1-carboxylate, 2.3

Tert-butyl4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate, 2.2 (300g, 1.102 mol) was dissolved in dry Acetonitrile (300 mL) and cooled to0° C. and Selectfluor (430 g, 1.21 mol) was added in portion wise over aperiod of 45 min. under N₂ atmosphere. After addition completed, thereaction mixture was allowed to room temperature and stirred for 2 h.The reaction was monitored by TLC (50% EtOAc/hexane). After completionof reaction by TLC the reaction mixture poured into ice cold saturatedbrine solution (300 mL) and extracted with EtOAc (2×200 mL). Thecombined EtOAc layers were washed with brine solution, water, dried overNa₂SO₄ and evaporated under vacuum. The residue was purified by columnchromatography on silica gel (10-40% EtOAc-Hexane) to afford tert-butyl3-fluoro-4-oxopiperidine-1-carboxylate 2.3 (170 g; 70.7%). ¹HNMR (CDCl₃,400 MHz): δ 4.88 (dd, 0.5H), 4.77 (dd, 0.5H), 4.47 (brs, 1H), 4.17 (ddd,1H), 3.25 (brs, 1H), 3.23 (ddd, 1H), 2.58 (m, 1H), 2.51 (m, 1H), 1.49(s, 9H).

Step-2.3: Synthesis of tert-butyl3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4

A solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate, 2.3 (80g, 0.368 mol) in THF (800 mL) was treated with L-Selectride (405 mL,0.405 mol, drop wise) at −78° C. under nitrogen atmosphere. Theresulting reaction mixture was stirred for 30 min. at the sametemperature, MeOH (45.1 mL, 1.105 mol) 1M NaOH (1104 mL, 1.105 mol) wereadded and the reaction was allowed to warm to 0° C. The reaction wasquenched by drop wise addition of H₂O₂ (125.1 mL, 1.843 mol). Thevolatiles were removed under vacuume and diluted with water (500 mL) andmethylene chloride (500 mL). After separation, the organic layer waswashed brine, dried over Na₂SO₄ and concentrated in vacuum to providethe desired product tert-butyl3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4 (63 g, 78%). ¹HNMR(CDCl₃, 400 MHz): δ 4.70-4.65 (m, 0.5H), 4.58-4.52 (m, 0.5H), 3.99-3.84(m, 2H), 3.82-3.58 (m, 1H), 3.55-3.27 (m, 1H), 3.18 (brs, 1H), 2.06(brs, 1H), 1.89-1.70 (m, 2H), 1.47 (s, 9H).

Step-2.4: Synthesis of tert-butyl3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate, 2.5

A solution of tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4(63 g, 0.287 mol) in anhydrous methylene chloride (630 mL) was treatedwith triethylamine (60 mL, 0.43 μmol) followed by methane sulfonylchloride (26.7 mL, 0.345 mol) at 0° C. under N2 atmosphere. The solutionwas allowed to warm slowly to ambient temperature and stirred for 14hours. The mixture was partitioned between saturated NaHCO₃ (400 mL) andmethylene chloride (400 mL). The aqueous layer was extracted withmethylene chloride (2×500 mL). The combined organic phases were washedwith 1N HCl, brine, dried over Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by silica gel chromatography, elutingwith 20-30% EtOAc/Hexane to provide the tert-butyl3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate, 2.5 (78 g,91%). ¹HNMR (CDCl₃, 400 MHz): δ 4.98-4.86 (m, 1H), 4.80-4.74 (m, 0.5H),4.67-4.63 (m, 0.5H), 3.92-3.45 (m, 3H), 3.44-3.25 (m, 1H), 3.08 (s, 3H),2.20-2.07 (m, 1H), 1.93-1.80 (m, 1H), 1.45 (s, 9H).

Step-2.5: Synthesis of tert-butyl4-azido-3-fluoropiperidine-1-carboxylate, 2.6

Sodium azide (68.2 g, 1.050 mol) was added to a solution of tert-butyl3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate, 2.5 (78 g,0.262 mol) in DMF (620 mL). The reaction mixture was heated at 100° C.for overnight. The mixture was cooled and diluted with 500 mL) water andmethylene chloride (500 mL). After separation, the organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated invacuum to provide the desired product tert-butyl4-azido-3-fluoropiperidine-1-carboxylate, 2.6 (62 g, 96% yield), whichwas used for the next reaction without any purification.

Step-2.6: Synthesis of tert-butyl4-amino-3-fluoropiperidine-1-carboxylate, 2.7

Pd/C 10% (12 g) was added to a solution of tert-butyl4-azido-3-fluoropiperidine-1-carboxylate, 2.6 (62 g, 0.254 mol) in EtOH(600 mL). The reaction was stirred under a hydrogen atmosphere (balloonpressure) for 48 hours. The mixture was filtered through celite-bed andconcentrated under reduced pressure to obtain the title compoundtert-butyl4-amino-3-fluoropiperidine-1-carboxylate, 2.7 (42 g, 75%yield). LCMS: m/z 218.8 (M+1).

Step-2.7: Synthesis of tert-butyl4-(benzylamino)-3-fluoropiperidine-1-carboxylate, 2.8

Benzaldehyde (34.0 g, 0.321 mol) was added to a solution of tert-butyl4-amino-3-fluoropiperidine-1-carboxylate, 2.7 (70 g, 0.32 mol) andacetic acid (10 mL) in ethanol (500 mL) and stirred for 30 min at roomtemperature. Sodiumcyanoborohydride (26.23 g, 0.417 mol) was added andstirred for 3 h. Reaction was quenched with saturated sodium bicarbonatesolution (200 mL) and extracted with dichloromethane (2×250 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was dissolved in a minimum amount of dichloromethane (200 mL)and pH adjusted to 3-4 by adding aqueous citric acid (124 g, 0.645 molin 1000 mL water). Layers were separated and aqueous layer was washedwith dichloromethane (3×250 mL). Separated aqueous layer pH was thenadjusted to 9-10 by using saturated Na₂CO₃ and extract with diethylether (2×500 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated to obtainthe crude product which was purified by as light yellow oil. The residuewas purified by silica gel chromatography by eluting with 10-15%EtOAc/hexane to provide the desired product tert-butyl4-(benzylamino)-3-fluoropiperidine-1-carboxylate, 2.8 (51 g, 51.52%yield). ¹HNMR (400 MHz, CDCl₃): δ 7.39-7.29 (m, 5H), 4.44-4.35 (m,0.5H), 4.32-4-10 (m, 1.5H), 3.98-3.85 (m, 2H), 3.80 (d, 1H), 2.97-2.77(m, 4H), 2.04-1.93 (m, 1H), 1.46 (s, 9H); LCMS: 92.34%, m/z=309.2 (M+1);HPLC: 95.46%; Chiral HPLC: 47.2% at 9.56 min. and 48.3% at 12.34 min.Column. AG/Chiral Pak AD-H/03, n-Hexane/EtOH (80:20).

Two enantiomers were separated by chiral preparative HPLC from Compound2.8. Amount: 42.5 g (load: 50 mg/ml). Conditions: Column: CHIRALPAK AD-H(250×50) mm.5 micron; Mobile Phase: ACN/EtOH (65:35); Parameters: flowrate 80 ml/min, column temp 25° C.

Peak-1: (3S,4S) tert-butyl4-(benzylamino)-3-fluoropiperidine-1-carboxylate, 2.9:

19.3 g, 45% yield. ¹HNMR (CDCl₃, 400 MHz): δ 7.35-7.25 (m, 5H),4.37-4.28 (m, 2H), 3.91-3.79 (dd, 3H), 2.86-2.82 (m, 3H), 1.99-1.97 (m,1H), 1.45 (s, 9H), 1.37-1.34 (m, 1H); LCMS: 99.43% m/z=309 (M+1); HPLC:99.9%, rt=10.0 min., (Column: CHIRALPAK AD-H (250×4.6) mm.5 micron,Mobile Phase: n-Hexane/EtOH/DEA 80/20/0.1, Parameters: flow rate 1ml/min, column temp 25° C., Detection: DAD220 nm).

Peak 2: (3R,4R) tert-butyl4-(benzylamino)-3-fluoropiperidine-1-carboxylate, 2.10

19.3 g, 46% yield. ¹HNMR (CDCl₃, 400 MHz,): δ 7.35-7.25 (m, 5H),4.37-4.28 (m, 2H), 3.91-3.79 (dd, 3H), 2.86-2.82 (m, 3H), 1.99-1.97 (m,1H), 1.45 (s, 9H), 1.37-1.34 (m, 1H); 99.64% m/z=309 (M+1); HPLC: 99.5%,rt=12.8 min. (Column: CHIRALPAK AD-H (250×4.6) mm.5 micron, MobilePhase: n-Hexane/EtOH/DEA 80/20/0.1, Parameters: flow rate 1 ml/min,column temp 25° C., Detection: DAD220 nm)

Step-2.8: Synthesis of (3S,4S)-tert-butyl4-amino-3-fluoropiperidine-1-carboxylate, 2.11

Pd/C 10% (4.5 g) was added to a solution of (3S,4S) tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate, 2.9 (19.1 g, 0.062 mol) in EtOH(500 mL). The reaction was stirred under hydrogen atmosphere (balloonpressure) for 16 hours at room temperature. After completion of reactionby TLC, the mixture was filtered through celite-bed and concentratedunder reduced pressure to obtain the title compound (3S,4S) tert-butyl4-amino-3-fluoropiperidine-1-carboxylate, 2.11 (12.6 g, 93% yield).¹HNMR (CDCl₃, 400 MHz): δ 4.33-4.14 (m, 1H), 4.13-4.02 (m, 2H),2.94-2.78 (m, 3H), 1.89-1.86 (m, 1H), 1.48 (s, 9H), 1.42-1.34 (m, 1H);LCMS: 100%, m/z 163.1 (M−55, tert-But); HPLC: 99.17%, rt=5.146 min.

Synthesis of (3R,4R)-tert-butyl4-amino-3-fluoropiperidine-1-carboxylate, 2.12

Pd/C 10% (4.5 g) was added to a solution of (3R,4R) tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate, 2.10 (19.6 g, 0.063 mol) inEtOH (500 mL). The reaction was stirred under hydrogen atmosphere(balloon pressure) for 16 hour. After completion of reaction by TLC, themixture was filtered through celite-bed and concentrated under reducedpressure to obtain the title compound (3R,4R) tert-butyl4-amino-3-fluoropiperidine-1-carboxylate, 2.12 (12.6 g, 92% yield).¹HNMR (CDCl₃, 400 MHz): δ 4.33-4.14 (m, 1H), 4.13-4.02 (m, 2H),2.94-2.78 (m, 3H), 1.89-1.86 (m, 1H), 1.48 (s, 9H), 1.42-1.34 (m, 1H);LCMS: 100%, m/z 163.1 (M−55, tert-But), HPLC: 99.62%, rt=5.214 min.

Alternative synthesis of tert-butyl(3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate, 4.6

Step-6.1: Synthesis of tert-butyl(3S,4R)-3-fluoro-4-(tosyloxy)piperidine-1-carboxylate, 4.3-1

Tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4 (6 g, 0.0273mol) in anhydrous DCM (100 mL) was treated with triethylamine (5.6 g,0.055 mol) and DMAP (0.35 g, 0.029 mol) followed by p-toluene sulfonylchloride (5.7 g, 0.03 mol) at 0° C. under nitrogen atmosphere. Theresulting mixture was allowed slowly to ambient temperature and stirredfor 16 h. The reaction mixture was poured into ice water, separated theorganic layer, washed with saturated NaHCO₃, brine solution, dried overNa₂SO₄, filtered and concentrated under vacuum. The residue was purifiedby silica gel chromatography (10-30% EtOAc/hexane), as the second elutedproduct 4.2-2, 4.1 g (major product, mixture of two enantiomers). HPLC(ZORBAX XDB): 98.35% at rt 5.3 min. Chiral HPLC: [(LUX AMYLOSE 5 micron2(250×4.60 mm), Hexane:EtOH (50:50)] shows two peaks at 7.27 min(Peak-1: 49.19% at rt) and at 11.406 min (Peak-2: 49.61% at rt). 1.6 gof the cis-isomer 4.2.2 was separated by chiral HPLC (column LUXAMYLOSE-2, flow rate: 20 ml/min, Solvent: n-Hexane/Ethanol (60:40)) and0.7 g of the 3S,4R-isomer 4.3-1 and 0.75 g of the 3R,4S-isomer 4.3-2were obtained.

Peak-1, 4.3-1: ¹H NMR (400 MHz, CDCl₃): δ 7.81-7.79 (d, 2H), 7.35-7.33(d, 2H), 4.83-4.52 (m, 2H), 4.05-3.55 (m, 2H), 3.50-3.05 (m, 2H), 2.44(s, 3H), 2.07-2.05 (m, 1H), 1.71-1.68 (m, 1H), 1.43 (s, 9H); LCMS:96.00%, m/z 274.1 (M-Boc+1); HPLC: 99.62%.

Peak-2, 4.3-2: ¹H NMR (400 MHz, CDCl₃): δ 7.81-7.79 (d, 2H), 7.35-7.33(d, 2H), 4.83-4.52 (m, 2H), 4.05-3.55 (m, 2H), 3.50-3.05 (m, 2H), 2.44(s, 3H), 2.07-2.05 (m, 1H), 1.71-1.68 (m, 1H), 1.43 (s, 9H); LCMS:94.48.0%, m/z 274 (M-Boc+1); HPLC: 97.64%.

Step-6.2: Synthesis of tert-butyl(3S,4S)-4-azido-3-fluoropiperidine-1-carboxylate, 4.4

Sodium azide (0.48 g, 0.0073 mol) was added to a solution of tert-butyl(3S,4R)-3-fluoro-4-(tosyloxy)piperidine-1-carboxylate, 4.3-1, Peak-1(0.7 g, 0.00187 mol) dissolved in DMF (15 mL). The reaction mixture washeated at 100° C. for 4 h. The mixture was cooled and diluted with waterand methylene chloride. After separation, the organic layer was driedover Na₂SO₄, filtered and concentrated in vacuum to provide the desiredproduct, 4.4 (0.4 g). The obtained product was taken for the nextreaction without any purification.

Step-6.3: Synthesis of tert-butyl(3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate, 4.6

Palladium on carbon 10% (0.1 g) was added to a solution of tert-butyl(3S,4S)-4-azido-3-fluoropiperidine-1-carboxylate, 4.4 (0.4 g, 0.00163mol) dissolved in EtOH (60 mL). The reaction was placed under a hydrogenatmosphere (40 psi pressure) for 16 h. The mixture was filtered throughcelite-bed and concentrated under reduced pressure to obtain the titlecompound tert-butyl (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate,4.6 (0.4 g crude).

The obtained product was taken for the next reaction without anypurification. After conversion of 4.6 with6-bromo-4-chloro-7-fluoro-3-nitroquinoline according to the proceduredetailed above in Step-1, (3S,4S)-tert-butyl4-((6-bromo-7-fluoro-3-nitroquinolin-4-yl)amino)-3-fluoropiperidine-1-carboxylatewas obtained with identical analytical data as provided above (i.e.HPLC, chiral HPLC and LCMS).

TABLE 1.2 IC50 μM Cascade HPLC Example Structure 1H NMR, LCMS, HPLC, rtMEK1 method  1A

¹H NMR (CDCl₃, 400 MHz): δ 9.33 (s, 1H), 8.65-8.64 (d, 2H), 8.08-8.05(d, 1H), 8.00-7.85 (m, 1H), 7.51-7.30 (m, 2H), 7.30-7.28 (dd, 1H),7.15-7.13 (m, 1H), 5.65-5.25 (m, 1H), 4.96-4.75 (m, 1H), 4.35-4.15 (m,2H), 3.92-3.74 (m, 2H), 3.35-3.15 (m, 1H), 3.05-2.85 (m, 2H), 2.80 (s,3H), 2.45-2.15 (m, 2H); LCMS: 97.59%, m/z = 565.1 (M + 1); HPLC: 98.80%,rt: 3.61 min., Column: ZORBAX XDB C18, 5 micro (4.6 × 150 mm); ChiralHPLC: 95.97%, rt = 21.37 min., Column: AG/CHIRALPAK AD-H/03. 0.005  1 1B

¹H NMR (CDCl₃, 400 MHz): δ 9.32 (s, 1H), 8.65-8.64 (d, 2H), 8.08-8.05(d, 1H), 7.95-7.85 (m, 1H), 7.50-7.40 (m, 2H), 7.31-7.28 (m, 1H),7.15-7.13 (m, 1H), 5.65-5.20 (m, 1H), 4.95-4.70 (m, 1H), 4.25-4.15 (m,2H), 3.90-3.70 (m, 2H), 3.35-3.15 (m, 1H), 3.01-2.85 (m, 2H), 2.80 (s,3H), 2.45-2.15 (m, 2H); LCMS: 99.77%, m/z = 564.90 (M + 1); HPLC:97.14%, rt: 3.61 min., Column: ZORBAX XDB C18, 5 micro (4.6 × 150 mm);Chiral HPLC: 97.23%, rt = 8.53 min., Column: AG/CHIRALPAK AD-H/03.0.138  1  2

¹H NMR (DMSO-d₆, 400 MHz): δ 9.21 (s, 1H), 8.73 (d, 2H), 8.42-8.35 (m,1H), 8.07 (d, 1H), 7.73 (d, 1H), 7.67 (d, 1H), 7.43 (dd, 1H), 7.37 (t,1H), 4.85-4.65 (m, 1H), 3.16 (s, 3H), 3.15-3.02 (m, 3H), 2.77 (s, 3H),2.68 (t, 2H), 2.34 (t, 2H), 2.32-2.22 (m, 3H), 2.10-1.95 (m, 2H); LCMS:90.41%, m/z = 547.10 (M + 1); HPLC: 96.15%, rt: 3.01 min. 0.726  1  3

¹H NMR (CDCl₃, 400 MHz): δ 9.26 (s, 1H), 8.63 (d, 2H), 8.35-8.25 (m,1H), 8.04 (d, 1H), 7.56 (d, 1H), 7.50 (d, 1H), 7.30 (dd, 1H), 7.14 (t,1H), 5.13-4.90 (m, 1H), 3.71-3.52 (m, 2H), 3.25-3.16 (m, 2H), 2.83 (s,3H), 2.69-2.50 (m, 4H), 2.41-2.29 (m, 2H), 2.32-1.99 (m, 2H); LCMS:100%, m/z = 533.4 (M + 1); HPLC: 97.69%, rt: 5.54 min. 0.104  3  4

¹H NMR (CDCl₃, 400 MHz): δ 9.26 (s, 1H), 8.64 (d, 2H), 8.04 (d, 1H),7.55 (d, 1H), 7.50 (s, 1H), 7.29 (d, 2H), 7.13 (t, 1H), 4.54-4.22 (m,4H), 2.99-2.79 (m, 6H), 2.61 (s, 3H), 2.34-2.22 (m, 2H), 2.18-1.85 (m,2H), 1.45-0.90 (m, 4H); LCMS: 97.45%, m/z = 573.6 (M + 1); HPLC: 96.81%,rt: 3.58 min. 0.309  4  5

¹H NMR (DMSO-d₆, 400 MHz): δ 9.20 (s, 1H), 8.71 (d, 2H), 8.55-8.47 (m,1H), 8.06 (d, 1H), 7.74 (d, 1H), 7.61 (s, 1H), 7.41-7.32 (m, 2H),5.45-5.33 (m, 1H), 3.85-3.77 (m, 2H), 3.09-2.92 (m, 2H), 2.89 (s, 3H),2.79 (s, 3H), 2.35-2.17 (m, 4H); LCMS: 98.33%, m/z = 567.4 (M + 1);HPLC: 94.22%, rt: 6.80 min. 0.04  1  6

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.64 (d, 2H), 8.26 (d, 1H),8.06 (d, 1H), 7.61-7.48 (m, 2H), 7.30 (d, 1H), 7.13 (t, 1H), 5.35-5.22(m, 1H), 5.02-4.92 (m, 1H), 4.59-4.50 (m, 1H), 4.09-3.98 (m, 1H),3.81-3.72 (m, 1H), 3.38-3.25 (m, 1H), 2.92-2.82 (m, 3H), 2.80 (s, 3H),2.41-2.22 (m, 2H), 1.34 (s, 3H); LCMS: 96.69%, m/z = 561.5 (M + 1);HPLC: 95.29%, rt: 3.37 min. 0.062  1  7

¹H NMR (DMSO-d₆, 400 MHz): δ 9.20 (s, 1H), 8.74 (d, 2H), 8.06 (d, 1H),7.75-7.68 (m, 1H), 7.67-7.62 (m, 1H), 7.43-7.33 (m, 3H), 4.30-4.19 (m,1H), 3.67-3.48 (m, 1H), 3.25-2.99 (m, 4H), 2.77 (s, 3H), 2.35-2.18 (m,6H), 1.30-1.21 (m, 3H); LCMS: 92.41%, m/z = 547.2 (M + 1); HPLC: 96.85%,rt: 3.43 min. 0.468  1  8

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.64 (d, 2H), 8.26 (bs, 1H),8.06 (d, 1H), 7.59 (d, 1H), 7.49 (s, 1H), 7.33-7.30 (dd, 1H), 7.16-7.13(m, 1H), 5.20 (m, 1H), 4.13 (d, 2H), 3.11 (m, 2H), 2.84 (s, 3H), 2.58(bs, 2H), 2.30 (bs, 3H), 1.03 (m, 4H); LCMS: 99.23%, m/z = 592.95 (M +1); HPLC: 97.12%, rt: 3.84 min. 0.015  1  9

¹H NMR (DMSO-d₆, 400 MHz): δ 9.20 (s, 1H), 8.72 (d, 2H), 8.46 (d, 1H),8.06 (d, 1H), 7.73 (d, 1H), 7.63 (s, 1H), 7.36-7.30 (dd, 2H), 5.31 ( m,1H), 3.85 (d, 2H), 3.23 (m, 2H), 2.78 (s, 3H), 2.19 (m, 2H), 2.30 (bs,3H), 1.35 (s, 6H); LCMS: 96.70%, m/z = 595.00 (M + 1); HPLC: 92.43%, rt:3.99 min. 0.103  1 10

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.64 (d, 2H), 8.31 (bs, 1H)8.06 (d, 1H), 7.57 (d, 1H), 7.50 (s, 1H), 7.32-7.30 (dd, 1H), 7.16 (dd,1H) 5.23 (m, 1H), 3.99 (d, 2H), 3.07 (bs, 2H), 2.84 (s, 8H), 2.20 (dd,2H), 2.30 (bs, 3H); LCMS: 99.20%, m/z = 595.95 (M + 1); HPLC: 98.14%,rt: 4.104 min. 0.213  1 11

¹H NMR (CDCl₃, 400 MHz): δ 9.28 (s, 1H), 8.64 (d, 2H), 8.46 (bs, 1H),8.06 (d, 1H), 7.52 (m, 1H), 7.49 (s, 1H), 7.30 (d, 1H), 7.13 (m, 1H),4.83 (m, 1H), 3.91 (s, 2H), 2.91 (bs, 4H), 2.81 (m, 5H), 2.58 (bs, 3H),2.16 (bs, 2H), 1.25 (s, 1H); LCMS: 98.22%, m/z = 560.35 (M + 1); HPLC:97.56%, rt: 2.594 min. 2.35  3 12

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.63 (d, 2H), 8.27 (d, 1H),8.06 (d, 1H), 7.61-7.53 (m, 1H), 7.49 (s, 1H), 7.32 (d, 1H), 7.12 (t,1H), 5.33-5.15 (m, 1H), 4.99 (d, 1H), 4.11 (d, 1H), 3.39-3.26 (m, 2H),2.81 (s, 3H), 2.80-2.69 (m, 2H), 2.41-2.25 (m, 2H), 2.18 (m, 3H); LCMS:98.09%, m/z = 531.4 (M + 1); HPLC: 95.65%, rt: 3.55 min. 0.212  1 13

¹H NMR (CDCl₃, 400 MHz): δ 9.31 (s, 1H), 8.89 (d, 1H), 8.81 (d, 1H),8.06 (d, 1H), 7.58 (d, 1H), 7.47 (d, 1H), 7.30 (d, 1H), 7.28 (d, 1H),7.19 (t, 1H), 4.62-4.51 (m, 1H), 3.21-3.07 (m, 2H), 3.05-2.95 (m, 2H),2.82-2.96 (m, 2H), 2.78 (s, 3H), 2.62-2.46 (m, 2H), 2.05-1.92 (m, 2H);LCMS: 99.57%, m/z = 546.6 (M + 1); HPLC: 96.97%, rt: 3.03 min. 0.515  114

¹H NMR (CDCl₃, 400 MHz): δ 9.28 (s, 1H), 8.65 (d, 2H), 8.25 (d, 1H),8.05 (d, 1H), 7.51 (d, 2H), 7.32-7.30 (m, 1H), 7.15-7.13 (m, 1H), 5.6(bs, 1H), 4.98-4.95 (m, 1H) 4.22-4.19 (m, 2H), 3.83 (d, 2H), 3.50 (d,1H), 3.26 (d, 1H), 2.90 (s, 1H), 2.81 (s, 4H), 2.34 (dd, , 2H); LCMS:99.8%, m/z = 547.4 (M + 1); HPLC: 95.8%, rt: 3.36 min. 0.0071 1 15

¹H NMR (CDCl₃, 400 MHz): δ 9.39 (s, 1H), 9.15 (s, 1H), 8.42 (d, 1H),8.33 (d, 1H), 8.06 (d, 1H), 7.53 (d, 1H), 7.46 (m, 1H), 7.26-7.24 (dd,1H), 7.01 (d, 1H), 3.49 (s, 2H), 3.32 (m, 2H), 2.95 (s, 3H), 2.81 (bs,1H), 2.57 (s, 3H), 2.50-2.47 (m, 3H), 2.08 (d, 2H), 2.0 (s, 3H); LCMS:97.08%, m/z = 547.2 (M + 1); HPLC: 99.6%, rt: 3.61 min. 0.016  1 16

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.64 (d, 2H), 8.33-8.25 (m,1H), 8.05 (d, 1H), 7.57 (d, 1H), 7.52 (d, 1H), 7.32 (dd, 1H), 7.14 (t,1H), 3.89-3.82 (m, 1H), 3.50-3.45 (m, 1H), 3.29 (d, 1H), 3.10 (d, 1H),2.84 (s, 3H), 2.61-2.50 (m, 2H), 2.43-2.13 (m, 6H), 1.14 (s, 3H); LCMS:99.31%, m/z = 547.05 (M + 1); HPLC: 90.33%, rt: 5.89 min. 0.059  1 17

¹H NMR (DMSO-d₆, 400 MHz): δ 9.33 (s, 1H), 9.29 (bs, 1H), 8.73 (m, 3H),8.08 (d, 1H), 7.64 (d, 1H), 7.46 (dd, 1H), 7.26-7.34 (dd, 2H), 4.32 (m,1H), 3.18-3.14 (q, 1H), 2.88 (m, 4H), 2.50 (s, 4H), 2.42-2.30 (m, 2H),1.99 (d, 2H), 1.92 (m, 2H); LCMS: 99.71%, m/z = 533.7 (M + 1); HPLC:98.32%, rt: 5.77 min. 0.093  3 18

¹H NMR (CDCl₃, 400 MHz): δ 9.37 (s, 1H), 9.01 (s, 1H), 8.42 (d, 1H),8.32 (s, 1H), 8.03 (d, 1H), 7.43 (d, 1H), 7.00-6.95 (m, 3H), 3.83 (s,3H), 3.38 (t, 2H), 2.96 (t, 2H), 2.71 (m, 1H), 2.58 (s, 3H), 2.56-2.48(m, 5H), 2.17 (d, 2H), 1.99 (s, 3H); LCMS: 99.41%, m/z = 543.7 (M + 1);HPLC: 99.00%, rt: 5.71 min. 0.013  3 19

¹H NMR (CDCl₃, 400 MHz): δ 9.37 (s, 1H), 8.95 (s, 1H), 8.64 (d, 1H),8.32 (s, 1H), 8.03 (d, 1H), 7.45 (d, 1H), 7.27 (s, 1H), 7.14 (t, 1H),7.01-6.91 (m, 2H), 3.83 (s, 3H), 3.49-3.39 (m, 2H), 2.99-2.88 (m, 2H),2.79-2.55 (m, 4H), 2.55 (t, 2H), 2.25-2.15 (m, 2H), 1.99 (s, 3H); LCMS:99.51%, m/z = 529.4 (M + 1); HPLC: 98.02%, rt: 5.66 min. 0.333  1 20

¹H NMR (CDCl₃, 400 MHz): δ 9.37 (s, 1H), 8.50-8.45 (m, 1H), 8.43 (d,1H), 8.28 (d, 1H), 8.05 (d, 1H), 7.43 (d, 1H), 7.01-6.95 (m, 3H),4.46-4.39 (m, 1H), 3.82 (s, 3H), 3.71 (d, 1H), 3.52-3.43 (m, 3H),2.92-2.69 (m, 2H), 2.57 (s, 3H), 2.55-2.50 (m, 2H), 2.06 (s, 3H), 1.34(d, 1.5H), 1.17 (d, 1.5H); LCMS: 94.08%, m/z = 571.7 (M + 1); HPLC:99.42%, rt: 4.03 min. 0.157  1 21

¹H NMR (CDCl₃, 400 MHz): δ 9.41 (s, 1H), 8.46-8.39 (m, 2H), 8.29 (s,1H), 8.10 (d, 1H), 7.53-7.49 (m, 2H), 7.30 (d, 1H), 7.01 (d, 1H),4.49-4.40 (m, 1H), 3.81-3.80 (m, 1H), 3.79-3.69 (m, 1H), 3.59-3.45 (m,2H), 2.83-2.67 (m, 2H), 2.57 (s, 3H), 2.43-2.35 (m, 2H), 2.50 (s, 3H),1.39-1.28 (m, 3H); LCMS: 95.93%, m/z = 575.4 (M + 1); HPLC: 97.48%, rt:4.42 min. 0.028  1 22

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.65 (d, 2H), 8.28 (s, 1H),8.05 (d, 1H), 7.60-7.46 (m, 2H), 7.30 (d, 1H), 7.16 (s, 1H), 5.48-5.23(m, 1H), 5.12-4.97 (m, 1H), 4.88-4.65 (m, 1H), 4.40-4.24 (m, 1H),4.10-3.71 (m, 3H), 3.48-3.00 (m, 5H), 2.80 (s, 4H), 2.48-2.20 (m, 3H);LCMS: 99.45%, m/z = 591.05 (M + 1); HPLC: 98.66%, rt: 3.13 min. 1.346  123

¹H NMR (CDCl₃, 400 MHz): δ 9.28 (s, 1H), 8.66 (d, 2H), 8.05 (d, 1H),7.60-7.57 (m, 1H), 7.52-7.48 (m, 1H), 7.32-7.26 (m, 2H), 7.21-7.15 (m,1H), 4.16-4.10 (m, 1H), 3.70-3.62 (m, 4H), 3.56-3.44 (m, 3H), 3.34-3.15(m, 3H), 2.80 (s, 4H), 2.32-2.18 (m, 4H); LCMS: 98.20%, m/z = 576.85(M + 1); HPLC: 98.61%, rt: 5.56 min. 0.322  3 24

¹H NMR (CDCl₃, 400 MHz): δ 9.38 (s, 1H), 8.48 (d, 1H), 8.43 (d, 1H),8.30 (s, 1H), 8.05 (d, 1H), 7.40 (d, 1H), 6.99-6.95 (m, 3H), 4.20-4.10(m, 2H), 4.01-3.94 (m, 1H), 3.81 (s, 3H), 3.73 (t, 1H), 3.63-3.52 (m,1H), 3.45-3.32 (m, 2H), 2.93-2.82 (m, 2H), 2.57 (s, 3H), 2.35-2.25 (m,1H), 2.25-2.16 (m, 1H), 2.07 (s, 3H); LCMS: 97.44%, m/z = 557.3 (M + 1);HPLC: 94.48%, rt: 3.90 min. 0.021  1 25

¹H NMR (CDCl₃, 400 MHz): δ 9.24 (s, 1H), 8.63 (d, 2H), 8.32-8.18 (m,1H), 8.01 (d, 1H), 7.58-7.48 (m, 2H), 7.31-7.27 (m, 1H), 7.12 (t, 1H),5.03-4.85 (m, 1H), 4.84-4.68 (m, 2H), 4.44-4.26 (m, 2H), 3.30-3.12 (m,1H), 3.06-2.84 (m, 2H), 2.88-2.67 (m, 6H), 2.58-2.32 (m, 1H), 2.39-2.02(m, 4H); LCMS: 53.64%, m/z = 559.35 (M + 1); HPLC: 98.77%, rt: 3.39 min.0.655  1 26

¹H NMR (CDCl₃, 400 MHz): δ 9.41 (s, 1H), 8.47-8.40 (m, 2H), 8.32 (s,1H), 8.09 (d, 1H), 7.49 (d, 1H), 7.46 (s, 1H), 7.29 (dd, 1H), 6.99 (d,1H), 4.30-4.20 (m, 1H), 4.16 (d, 1H), 4.03 (d, 1H), 3.73 (bs, 1H),3.56-3.30 (m, 3H), 2.90-2.79 (m, 2H), 2.57 (s, 3H), 2.32-2.19 (m, 2H),2.08 (s, 3H); LCMS: 99.11%, m/z = 561.2 (M + 1); HPLC: 99.47%, rt: 3.83min. 0.0043 1 27

¹H NMR (CDCl₃, 400 MHz): δ 9.42 (s, 1H), 8.66-8.65 (d, 2H), 8.45-8.40(d, 1H), 8.3 (s, 1H), 8.15-8.1 (d, 1H), 7.55-7.50 (d, 2H), 7.35-7.30 (d,1H), 7.20-7.10 (t, 1H), 4.50-4.40 (t, 1H), 3.90-3.70 (m, 2H), 3.64-3.45(m, 2H), 2.70-2.6 (m, 2H), 2.45-2.30 (bs, 2H), 2.09 (s, 3H), 1.40-1.15(dd, 3H); LCMS: 93.23%, m/z = 561.4 (M + 1); HPLC: 98.04%, rt: 3.07 min.0.073  3 28

¹H NMR (CDCl₃, 400 MHz): δ 9.26 (s, 1H), 8.43 (d, 1H), 8.24 (d, 1H),8.04 (d, 1H), 7.48 (d, 1H), 7.30-7.25 (m, 2H), 6.98 (d, 1H), 4.99-4.90(m, 1H), 4.19 (d, 1H), 3.76 (d, 1H), 3.31-3.19 (m, 2H), 2.95-2.79 (m,4H), 2.79 (s, 3H), 2.55 (s, 3H), 1.89-1.70 (m, 2H); LCMS: 87.67%, m/z =561.1 (M + 1); HPLC: 99.29%, rt: 2.57 min. 0.0037 5 29

¹H NMR (CDCl₃, 400 MHz): δ 9.26 (s, 1H), 8.43 (d, 1H), 8.26 (d, 1H),8.05 (d, 1H), 7.50 (s, 2H), 7.30-7.26 (m, 1H), 7.98 (d, 1H), 5.35-5.20(m, 1H), 4.98 (d, 1H), 4.60-4.49 (m, 1H), 4.11-3.93 (m, 1H), 3.85-3.69(m, 1H), 3.39-3.20 (m, 1H), 2.95-2.82 (m, 1H), 2.80 (s, 3H), 2.56 (s,3H), 2.42-2.22 (m, 2H), 1.72-1.59 (m, 2H), 1.42-1.29 (m, 3H); LCMS:90.37%, m/z = 575.03 (M + 1); HPLC: 95.04%, rt: 3.74 min. 0.019  1 30

¹H NMR (DMSO-d₆, 300 MHz): δ 9.20 (s, 1H), 8.71 (d, 2H), 8.40 (d, 1H),8.05 (d, 1H), 7.75-7.59 (m, 2H), 7.41 (d, 1H), 7.36 (t, 1H), 6.19-5.92(m, 1H), 5.90-5.65 (m, 1H), 5.41-5.15 (m, 1H), 5.10-4.79 (m, 1H), 4.19(d, 2H), 3.01-2.85 (m, 2H), 2.77 (s, 3H), 2.22-1.85 (m, 3H); LCMS:99.43%, m/z = 532.3 (M + 1); HPLC: 96.63%, rt: 3.16 min. 0.011  3 31

¹H NMR (DMSO-d₆, 400 MHz): δ 9.19 (s, 1H), 8.51 (d, 1H), 8.40 (m, 1H),8.05 (d, 1H), 7.72-7.54 (m, 2H), 7.42-7.36 (m, 1H), 7.22 (d, 1H),6.10-5.50 (m, 3H), 5.10-4.80 (m, 1H), 4.20 (m, 2H), 2.92 (t, 2H), 2.77(s, 3H), 2.46 (s, 3H), 2.10-1.90 (m, 3H); LCMS: 99.6%, m/z = 546.5 (M +1); HPLC: 96.6%, rt: 6.26 min. 0.003  1 32

¹H NMR (CDCl₃, 400 MHz): δ 9.52 (s, 1H), 8.64 (d, 1H), 8.55 (d, 1H),8.22 (d, 1H), 7.78 (d, 1H), 7.63 (s, 1H), 7.40 (s, 1H), 7.26 (d, 1H),3.89-3.81 (m, 1H), 3.79-3.50 (m, 4H), 3.16-3.02 (m, 2H), 2.99-2.80 (m,2H), 2.88 (s, 3H), 2.48 (s, 3H), 2.45-2.20 (m, 3H); LCMS: 96.64%, m/z =581.1 (M + 1); HPLC: 96.81%, rt: 2.68 min. 0.032  5 33

¹H NMR (CDCl₃, 400 MHz): δ 9.43 (s, 1H), 8.67-8.66 (d, 2H), 8.44-8.42(d, 1H), 8.33 (s, 1H), 8.12-8.1 (d, 1H), 7.51-7.49 (m, 2H), 7.32-7.27(dd, 1H), 7.17-7.15 (t, 1H), 4.21-4.16 (m, 2H), 4.08-4.04 (d, 1H), 3.71(s, 1H), 3.60-3.50 (m, 1H), 3.44-3.35 (m, 2H), 2.86-2.83 (bs, 2H),2.28-2.24 (t, 2H), 2.09 (s, 3H); LCMS: 99.69%, m/z = 547.0 (M + 1);HPLC: 99.06%, rt: 3.72 min. 0.028  1 34

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.64 (d, 2H), 8.27 (d, 1H),8.06 (d, 1H), 7.59-7.49 (m, 2H), 7.31 (d, 1H), 7.14 (t, 1H), 5.45-5.33(m, 1H), 5.03-4.93 (m, 1H), 4.61-4.52 (m, 1H), 4.12-3.98 (m, 1H), 3.79(d, 1H), 3.40-3.25 (m, 1H), 2.95-2.83 (m, 2H), 2.81 (s, 3H), 2.45-2.33(m, 2H), 1.49-1.31 (m, 3H); LCMS: 98.63%, m/z = 561.4 (M + 1); HPLC:96.79%, rt: 3.38 min. 0.088  1 35

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.43 (d, 1H), 8.07 (d, 1H),8.06 (d, 1H), 7.60-7.51 (m, 2H), 7.30-7.26 (m, 1H), 7.00 (d, 1H),5.39-5.29 (m, 1H), 4.10-4.00 (m, 1H), 3.80-3.30 (m, 2H), 2.90-2.60 (m,2H), 2.81 (s, 3H), 2.56 (s, 3H), 2.40-2.10 (m, 3H), 1.35-1.33 (m, 4H);LCMS: 98.74%, m/z = 575.60 (M + 1); HPLC: 90.71%, rt: 3.50 min. 0.019  136

1H NMR (CDCl₃, 400 MHz): δ 9.25 (s, 1H), 8.41 (d, 1H), 8.02 (d, 1H),7.54 (d, 1H), 7.48 (d, 1H), 7.30-7.24 (m, 2H), 6.98 (d, 1H), 3.75-3.30(m, 3H), 3.25-3.15 (m, 2H), 2.82 (s, 3H), 2.70-2.59 (m, 4H), 2.55 (s,3H), 2.42-2.30 (m, 2H), 2.25-1.90 (m, 2H); LCMS: 98.76%, m/z = 547.2(M + 1); HPLC: 95.40%, rt: 3.02 min. 0.026  1 37

¹H NMR (CDCl₃, 400 MHz): δ 9.39 (s, 1H), 8.73 (d, 1H), 8.40 (d, 1H),8.35 (s, 1H), 8.05 (d, 1H), 7.40 (d, 1H), 7.18 (d, 1H), 6.99-6.91 (m,2H), 4.74 (s, 2H), 3.97 (d, 2H), 3.81 (s, 3H), 3.25-2.98 (m, 4H), 2.56(s, 3H), 2.08 (s, 3H), 1.94 (d, 2H); LCMS: 99.54%, m/z = 542.4 (M + 1);HPLC: 98.15%, rt: 3.30 min. 0.0027 1 38

¹H NMR (CDCl₃, 400 MHz): δ 9.38 (s, 1H), 8.70 (d, 1H), 8.61 (d, 2H),8.34 (s, 1H), 8.04 (d, 1H), 7.41 (dd, 1H), 7.11 (t, 1H), 6.95-6.90 (m,2H), 4.73 (s, 2H), 3.95 (d, 2H), 3.81 (s, 3H), 3.20 (t, 2H), 3.11-2.94(m, 2H), 2.07 (s, 3H), 1.96 (d, 2H); LCMS: 98.83%, m/z = 528.3 (M + 1);HPLC: 98.72%, rt: 3.06 min. 0.0046 1 39

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.64 (d, 2H), 8.27 (d, 1H),8.06 (d, 1H), 7.61-7.52 (m, 1H), 7.51 (d, 1H), 7.32 (d, 1H), 7.14 (t,1H), 5.35-5.16 (m, 1H), 5.15-4.92 (m, 1H), 4.09-3.99 (m, 1H), 3.61-3.51(m, 2H), 3.33-3.20 (m, 2H), 2.81 (s, 3H), 2.41-2.19 (m, 4H); LCMS:95.70%, m/z = 546.1 (M + 1); HPLC: 92.16%, rt: 3.39 min. 0.455  1 40

¹H NMR (CDCl₃, 400 MHz): δ 9.24 (s, 1H), 8.42 (d, 1H), 8.25 (d, 1H),8.02 (d, 1H), 7.60-7.40 (m, 2H), 7.30-7.26 (m, 1H), 6.97 (s, 1H), 5.23(s, 1H), 4.97 (d, 1H), 4.01 (d, 1H), 3.52-3.24 (m, 4H), 2.78 (s, 3H),2.54 (s, 3H), 2.28-2.02 (m, 6H); LCMS: 97.47%, m/z = 560.1 (M + 1);HPLC: 95.25%, rt: 2.94 min. 0.186  1 41

¹H NMR (DMSO-d₆, 400 MHz): δ 9.34 (s, 1H), 8.68 (s, 1H), 8.53 (d, 1H),8.44 (d, 1H), 8.11 (d, 1H), 7.67 (d, 1H), 7.60 (s, 1H), 7.37 (d, 1H),7.23 (d, 1H), 5.58-5.48 (m, 1H), 4.49-4.38 (m, 1H), 4.13 (d, 2H),4.12-4.01 (m, 1H), 3.98-3.87 (m, 1H), 3.82-3.69 (m, 1H), 3.58-3.43 (m,2H), 3.23-3.10 (m, 1H), 2.81-2.63 (m, 2H), 2.47 (s, 3H), 2.35-2.15 (m,2H); LCMS: 97.48%, m/z = 577.4 (M + 1); HPLC: 96.69%, rt: 3.51 min.0.022  1 42

¹H NMR (CDCl₃, 400 MHz): δ 9.25 (s, 1H), 8.62 (d, 2H), 8.29 (s, 1H),8.24 (d, 1H), 7.61-7.46 (m, 2H), 7.30 (d, 1H), 7.13 (t, 1H), 5.35-5.16(m, 1H), 4.99-4.87 (m, 1H), 4.30-4.19 (m, 2H), 3.52-3.38 (m, 2H), 2.26(s, 3H), 2.80 (s, 3H), 2.41-1.89 (m, 5H); LCMS: 93.19%, m/z = 561.1 (M +1); HPLC: 98.48%, rt: 3.63 min. 0.085  1 43A

¹HNMR (CDCl₃, 400 MHz): δ 9.30 (s, 1H), 8.66 (d, 2H), 8.31 (d, 1H), 8.10(d, 1H), 7.55-7.48 (m, 2H), 7.33 (dd, 1H), 7.16 (t, 1H), 5.48-5.31 (m,1H), 5.10-4.95 (m, 1H), 4.52-4.31 (m, 1H), 3.38-3.24 (m, 1H), 2.95-2.85(m, 2H), 2.83 (s, 3H), 2.50-2.18 (m, 3H), 1.70-1.49 (m, 4H); LCMS:94.93%, m/z = 563.2 (M⁺); HPLC: 97.94%, rt: 28.93 min. 0.06  1 43B

¹HNMR (CDCl₃, 400 MHz): δ 9.31 (s, 1H), 8.65 (d, 2H), 8.33 (d, 1H), 8.12(d, 1H), 7.61-7.49 (m, 2H), 7.32 (dd, 1H), 7.16 (t, 1H), 5.45-5.17 (m,1H), 5.04-4.88 (m, 1H), 4.50-4.31 (m, 1H), 3.40-3.22 (m, 1H), 2.95-2.85(m, 2H), 2.84 (s, 3H), 2.56-2.19 (m, 3H) 1.72-1.52 (m, 4H); LCMS:98.75%, m/z = 563.2 (M⁺); HPLC: 94.64%, rt: 32.55 min. 0.547  1 44

¹HNMR (CDCl₃, 400 MHz): δ 9.31 (s, 1H), 8.28-8.17 (m, 1H), 8.05 (d, 1H),7.79 (t, 1H), 7.45 (s, 1H), 7.28-7.24 (m, 2H), 7.07 (d, 1H), 7.00 (d,1H), 5.08-4.96 (m, 1H), 4.93-4.77 (m, 1H), 4.75-4.16 (m, 1H), 4.63-4.54(m, 1H), 4.31-4.21 (m, 2H), 3.86-3.75 (m, 2H), 3.33-3.21 (m, 2H),2.95-2.83 (m, 3H), 2.81 (s, 3H), 2.18-1.96 (m, 2H); LCMS: m/z = 83.62%,576.45 (M⁺); HPLC: 98.59%, rt: 3.58 min. 0.002  1 45

¹HNMR (CDCl₃, 300 MHz): δ 9.26 (s, 1H), 8.64 (d, 2H), 8.35-8.25 (m, 1H),8.10 (d, 1H), 7.59-7.46 (m, 2H), 7.31 (dd, 1H), 7.15 (t, 1H), 5.15-4.95(m, 2H), 4.30 (d, 2H), 4.02-3.84 (m, 2H), 3.10 (t, 2H), 2.82 (s, 3H),2.54-2.12 (m, 4H); LCMS: 94.87%, m/z = 614.5 (M + 1); HPLC: 96.46%, rt:3.64 min. 0.191  1 46

¹HNMR (CDCl₃, 400 MHz): δ 9.31 (s, 1H), 8.56 (d, 1H), 8.34-8.14 (m, 2H),7.64-7.45 (m, 2H), 7.32 (dd, 1H), 7.01-6.98 (m, 1H), 5.45-4.77 (m, 2H),4.41-4.10 (m, 2H), 3.85 (d, 1H), 3.47-3.29 (d, 1H), 3.04-3.87 (m, 2H),2.84 (s, 3H), 2.54-2.00 (m, 4H); LCMS: 97.87%, m/z = 565.45 (M + 1);HPLC; 94.75%, rt: 3.74 min. 0.01  1 47

¹HNMR (DMSO-d₆, 400 MHz): δ 9.20 (s, 1H), 8.54-8.19 (m, 1H), 8.14-8.03(m, 2H), 7.82-7.66 (m, 1H), 7.59-7.54 (m, 1H), 7.36-7.28 (m, 1H), 7.09(d, 1H), 6.98 (dd, 1H), 5.48-5.24 (m, 1H), 4.65-4.55 (m, 2H), 4.16-4.03(m, 2H), 3.97-3.86 (m, 2H), 2.95-2.80 (m, 2H), 2.77 (s, 3H), 2.28-2.01(m, 2H); LCMS: 98.13%, m/z = 564.20 (M + 1); HPLC: 97.09%, rt: 3.97 min.0.0017 3 48

¹HNMR (DMSO-d₆, 400 MHz): δ 9.18 (s, 1H), 8.62 (s, 1H), 8.32 (s, 1H),8.05 (d, 1H), 7.78-67 (m, 1H), 7.63-7.55 (m, 1H), 7.41-7.53 (m, 1H),5.50-4.92 (m, 1H), 4.66-4.54 (m, 2H), 4.16-4.02 (m, 2H), 3.96-3.87 (m,2H), 2.96-2.82 (m, 1H), 2.78 (s, 3H), 2.47 (s, 3H), 2.49-2.05 (m, 3H);LCMS: 100%, m/z = 578.9 (M⁺); HPLC: 97.87%, rt: 4.27 min. 0.011  1 49

¹HNMR (CDCl₃, 400 MHz): δ 9.31 (d, 1H), 8.68-8.60 (m, 2H), 8.34 (d,0.5H), 8.12-8.01 (m, 1.5H), 7.59 (d, 0.5H), 7.54-7.45 (m, 1.5H),7.37-7.30 (m, 1H), 7.18-7.11 (m, 1H), 5.69-5.16 (m, 2H), 4.99-4.61 (m,3H), 4.37-4.25 (m, 0.5H), 4.01-3.88 (m, 0.5H), 3.50 (d, 1H), 3.03-2.90(m, 2H), 2.88 (s, 1.5H), 2.81 (s, 1.5H), 2.50-2.33 (m, 1H), 2.22 (s,1.5H), 2.07 (s, 1.5H); LCMS: 99.24%, m/z = 608.45 (M + 1); HPLC: 99.76%,rt: 4.32 min. 0.232  1 50

¹HNMR (CDCl₃, 300 MHz): δ 9.29 (d, 1H), 8.65-8.56 (m, 2H), 8.31-8.18 (m,1H), 8.12-8.02 (m, 1H), 7.60-7.41 (m, 2H), 7.35-7.28 (m, 1H), 7.20-7.17(m, 1H), 5.00-5.20 (m, 1.5H), 4.75-4.57 (m, 0.5H), 4.47-4.33 (m, 1H),4.13-4.00 (m, 1H), 3.09-2.95 (m, 2H), 2.96 (s, 1.5H), 2.89 (s, 1.5H),2.77 (s, 1.5H), 2.71 (s, 1.5H), 2.65-2.50 (m, 1H), 2.43-2.15 (m, 1H);LCMS: 97.71%, m/z = 585.1 (M⁺); HPLC: 98.58%, rt: 3.83 min. 0.012  1 51

¹HNMR (CDCl₃, 300 MHz): δ 9.32 (s, 1H), 8.85 (d, 1H), 8.08 (d, 2H),7.95-7.87 (m, 1H), 7.52 (s, 1H), 7.46 (d, 1H), 7.32 (dd, 1H), 5.69-5.20(m, 2H), 4.95-4.68 (m, 1H), 4.20-4.05 (m, 1H), 3.84-3.20 (m, 1H),3.40-3.16 (m, 2H), 2.98-2.82 (m, 2H), 2.79 (s, 3H), 2.43-2.13 (m, 2H);LCMS: 94.03%, m/z = 633.1 (M + 1); HPLC: 97.16%, rt: 4.17 min. 0.001  352

¹HNMR (DMSO-d₆, 300 MHz): δ 9.21 (d, 1H), 8.80-8.56 (m, 2H), 8.15-7.95(m, 2H), 7.78-7.48 (m, 2H), 7.44-7.24 (m, 2H), 5.71-5.07 (m, 2H),4.95-4.78 (m, 1H), 4.55-4.45 (m, 1H), 4.38-4.10 (m, 1H), 3.95-3.73 (m,2H), 3.09 (s, 3H), 2.89-2.68 (m, 4H), 2.39-2.15 (m, 2H); LCMS: 93.15%,m/z = 579.2 (M + 1); HPLC: 99.63%, rt: 3.99 min. 0.009  1 53

¹HNMR (CDCl₃, 300 MHz): δ 9.32 (s, 1H), 8.30 (s, 1H), 8.06 (d, 1H),7.95-7.86 (m, 1H), 7.58-7.35 (m, 2H), 7.30-7.26 (m, 1H), 5.71-5.08 (m,2H), 4.96-4.70 (m, 1H), 4.32-4.05 (m, 2H), 3.85-3.68 (m, 1H), 3.64-3.52(m, 1H), 3.35-3.13 (m, 1H), 3.00-2.87 (m, 2H), 2.79 (s, 3H), 2.56 (d,3H), 2.28-2.10 (m, 1H); LCMS: 98.34%, m/z = 597.1 (M + 1); HPLC: 98.81%,rt: 3.95 min. 0.0062 3 54

¹HNMR (CDCl₃, 300 MHz): δ 9.27 (s, 1H), 8.33 (d, 1H), 8.24 (d, 1H), 8.05(d, 1H), 7.58-7.50 (m, 1H), 7.48 (d, 1H), 7.27 (dd, 1H), 7.97 (s, 1H),5.35-5.24 (m, 0.5H), 4.97 (d, 1H), 4.88-4.75 (m, 0.5H), 4.35-4.14 (m,1.5H), 3.82 (d, 1H), 3.15-3.04 (m, 0.5H), 3.33-3.21 (m, 1H), 2.96-2.83(m, 2H), 2.81 (s, 3H), 2.41-2.25 (m, 2H), 2.06-1.98 (m, 2H), 1.28-1.10(m, 5H); LCMS: 93.42%, m/z = 587.2 (M⁺); HPLC: 97.30%, rt: 3.89 min.0.0015 4 55

¹HNMR (DMSO-d₆, 400 MHz): δ 9.19 (d, 1H), 8.71 (d, 2H), 8.09-8.02 (m,1H), 7.76-7.64 (m, 1H), 7.58 (d, 1H), 7.43 (d, 1H), 7.38-7.32 (m, 2H),5.65-5.51 (m, 0.3H), 5.19-5.05 (m, 0.7H), 3.82-3.54 (m, 2H), 3.30-3.21(m, 2H), 3.10-2.97 (m, 2H), 2.8-2.74 (m, 4H), 2.45-2.28 (m, 1H); LCMS:m/z = 93.88%, 538.40 (M + 1); HPLC: 95.13%, rt: 3.55 min. 0.047  1 56

¹HNMR (DMSO-d₆, 300 MHz): δ 9.21 (d, 1H), 8.73 (d, 2H), 8.62-8.34 (m,1H), 8.15-8.05 (m, 1H), 7.81-7.73 (m, 1H), 7.70-7.66 (m, 1H), 7.41 (dd,1H), 7.35 (t, 1H), 5.89-5.42 (m, 1H), 5.35-5.28 (m, 0.5H), 5.18-5.12 (m,0.5H), 4.25-4.04 (m, 2H), 3.87-3.42 (m, 2H), 3.31-2.99 (m, 2H), 2.80 (s,2.7H), 2.76 (s, 0.3H); LCMS: 53.05% +29.00%, m/z = 508.1 (M); HPLC:72.37%, rt: 3.97 min, 27.62%, rt: 3.87 min. 0.28  3 57

¹H NMR (CDCl₃, 400 MHz): δ 9.32 (s, 1H), 8.69-8.67 (d, 1H), 8.40-8.39(d, 1H), 8.08-8.05 (d, 1H), 7.52-7.45 (m, 2H), 7.28-7.25 (m, 1H),7.01-7.00 (d, 1H), 5.76-5.63 (m, 1H), 4.71-4.63 (m, 1H), 3.54-3.35 (m,3H), 3.01-2.93 (m, 2H), 2.81-2.67 (m, 5H), 2.56 (s, 3H), 2.24-2.17 (m,1H); LCMS: 99.48%, m/z = 559.7 (M + 1); HPLC: 99.10%, rt = 4.79 min.;Column: ZORBAX XDB C18, 5 micro (4.6 × 150 mm); Chiral HPLC: 99.64%, rt= 23.05 min.; Column: AG/CHIRALPAK AD-H/03. 0.019  1 58

¹H NMR (CDCl₃, 400 MHz): δ 9.32 (s, 1H), 8.69-8.67 (d, 1H), 8.40-8.39(d, 1H), 8.08-8.05 (d, 1H), 7.52-7.50 (d, 1H), 7.45-7.44 (d, 1H),7.28-7.25 (m, 1H), 7.01-7.00 (d, 1H), 5.85-5.55 (m, 1H), 4.71-4.63 (m,1H), 3.50-3.36 (m, 3H), 3.0-2.95 (m, 2H), 2.77 (s, 3H), 2.74-2.68 (m,2H), 2.67 (s, 3H), 2.24-2.18 (m, 1H); LCMS: 98.75%, m/z = 559.8 (M + 1);HPLC: 99.47%, rt = 4.512 min.; Column: ZORBAX XDB C18, 5 micro (4.6 ×150 mm); Chiral HPLC: 99.31%, rt = 18.13 min.; Column: AG/CHIRALPAKAD-H/03. 0.003  1 59

¹H NMR (CDCl₃, 400 MHz): δ 9.29 (s, 1H), 8.92 (bs, 1H), 8.06 (d, 1H),7.61 (d, 1H), 7.41 (s, 1H), 7.26-7.22 (dd, 1H), 7.05 (s, 1H), 5.20 (m,1H), 3.50 (s, 2H), 3.11 (d, 2H), 2.80 (bs, 4H), 2.62 (m, 6H), 2.05 (bs,2H); LCMS: 94.69%, m/z = 566.7 (M + 1); HPLC: 95.03%, rt: 4.70 min.0.018  1 60

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.9 (bs, 1H), 8.04 (d, 2H),7.53 (d, 1H), 7.37 (s, 1H), , 7.18 (dd, 1H), 5.86 (s, 1H), 3.53 (s,−3H), 3.06-3.05 (m, 2H), 2.80 (bs, 4H), 2.66-2.60 (t, 3H), 1.28 (d, 5H);LCMS: 93.39%, m/z = 558.30 (M + 1); HPLC: 91.5%, rt: 3.63 min. 0.113  161

¹H NMR (CDCl₃, 400 MHz): δ 9.30 (s, 1H), 8.64-8.60 (m, 3H), 8.03-8.00(d, 1H), 7.41-7.39 (d, 1H), 7.15-7.13 (m, 1H), 7.01-6.94 (m, 2H),5.79-5.65 (m, 1H), 4.70-4.62 (m, 1H), 3.83 (s, 3H), 3.57-3.47 (m, 3H),3.03-2.95 (m, 2H), 2.78 (s, 3H), 2.72-2.70 (m, 2H), 2.25-2.22 (m, 1H);LCMS: 96.23%, m/z = 542.5 (M + 1); HPLC: 98.31%, rt = 6.63 min.; Column:ZORBAX XDB C18, 5 micro (4.6 × 150 mm); Chiral HPLC: 97.35%, rt = 18.522min.; Column: LUX 5 u AMYLOSE-2 (150 × 4.60 MM), 5 Micron. 0.211  1 62

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.62-8.57 (m, 3H), 8.00-7.97(d, 1H), 7.38-7.36 (d, 1H), 7.12-7.10 (m, 1H), 6.93-6.91 (d, 2H),5.77-5.62 (m, 1H), 4.68-4.60 (m, 1H), 3.81 (s, 3H), 3.44-3.33 (m, 3H),3.02-2.97 (m, 2H), 2.78 (s, 3H), 2.72-2.65 (m, 2H), 2.22-2.17 (m, 1H);LCMS: 95.36%, m/z = 542.5 (M + 1); HPLC: 96.54%, rt = 6.63 min.; Column:ZORBAX XDB C18, 5 micro (4.6 × 150 mm); Chiral HPLC: 96.18%, rt = 20.44min.; Column: LUX 5 u AMYLOSE-2 (150 × 4.60 MM), 5 Micron. 0.0037 1 63

¹H NMR (CDCl₃, 400 MHz): δ 9.26 (s, 1H), 8.21-8.20 (d, 1H), 8.04-8.01(d, 1H), 7.30 (s, 1H), 7.28-7.26 (m, 2H), 7.17-7.16 (d, 1H), 7.04-7.01(dd, 1H), 6.26-6.22 (t, 1H), 5.35-5.30 (m, 1H), 4.90-5.00 (m, 2H),4.25-4.28 (m, 1H), 3.89-3.78 (m, 1H), 3.66 (s, 3H), 3.39-3.20 (m, 1H),3.02-2.90 (m, 1H), 2.80 (s, 3H), 2.41-2.25 (m, 4H); LCMS: 94.13%, m/z =576.3 (M + 1); HPLC: 93.22%, rt: 3.28 min. 0.0085 1 64

¹H NMR (DMSO-d₆, 400 MHz): δ 9.35 (s, 1H), 8.73 (d, 3H), 8.55 (d, 1H),8.12 (d, 1H), 7.68 (d, 1H), 7.64 (d, 1H), 7.41 (dd, 1H), 7.39 (t, 1H),5.91 (s, 2H), 3.65-3.56 (m, 2H), 3.44-3.32 (m, 2H), 2.52-2.50 (m, 2H),2.25-2.15 (m, 2H), 1.94 (s, 3H); LCMS: 98.76%, m/z = 532.05 (M + 1);HPLC: 99.18%, rt: 3.90 min. 0.0053 1 65

¹H NMR (DMSO-d₆, 400 MHz): δ 9.35 (s, 1H), 8.72 (s, 1H), 8.53 (d, 2H),8.11 (d, 1H), 7.66 (d, 1H), 7.59 (d, 1H), 7.38 (dd, 1H), 7.23 (d, 1H),5.88 (s, 2H), 3.65-3.56 (m, 2H), 3.44-3.32 (m, 2H), 2.62-2.50 (m, 2H),2.50 (s, 3H), 2.25-2.15 (m, 2H), 1.94 (s, 3H); LCMS: 100%, m/z = 545.90(M + 1); HPLC: 98.82%, rt: 4.10 min. 0.0024 1 66

¹H NMR (CDCl₃, 400 MHz): δ 9.42 (s, 1H), 8.44-8.42 (d, 1H), 8.32 (s,1H), 8.11-8.08 (d, 1H), 7.528-7.523 (d, 1H), 7.47-7.45 (d, 1H),7.33-7.31 (dd, 1H), 6.40 (s, 1H), 4.3-4.1 (m, 2H), 3.97 (s, 3H), 3.7 (s,1H), 3.56-3.3 (m, 4H), 2.90-2.75 (bs, 2H), 2.44 (s, 3H), 2.30-2.15 (bs,2H), 2.09 (s, 3H); LCMS: 93.21%, m/z = 591.5 (M + 1); HPLC: 98.58%, rt:4.62 min. 0.01  1 67

¹H NMR (CDCl₃, 400 MHz): δ 9.31 (s, 1H), 8.43 (d, 1H), 8.32 (d, 1H),8.13 (d, 1H), 7.49 (s, 2H), 7.33 (d, 1H), 7.00 (t, 1H), 5.41-5.18 (m,1H), 5.02-4.82 (m, 1H), 4.35-4.15 (m, 3H), 3.55-3.01 (m, 5H), 2.85-2.65(m, 5H), 2.56 (s, 3H), 2.40-2.18 (m, 2H); LCMS: 96.42%, m/z = 575.4 (M +1); HPLC: 95.10%, rt: 3.67 min. 0.053  1 68

¹H NMR (CDCl₃, 400 MHz): δ 9.32 (s, 1H), 8.44 (d, 1H), 8.06 (d, 1H),7.94 (s, 1H), 7.60-7.36 (m, 2H), 7.29 (s, 1H), 6.99 (d, 1H), 5.65-5.21(m, 2H), 4.95-4.70 (m, 1H), 4.30-4.11 (m, 2H), 3.92-3.73 (m, 2H),3.40-3.15 (m, 1H), 3.05-2.75 (m, 5H), 2.57 (s, 3H), 2.29-2.10 (m, 1H);LCMS: 99.65%, m/z = 579.25 (M+); HPLC: 97.96%, rt: 3.62 min. 0.0047 1 69

¹H NMR (CDCl₃, 400 MHz): δ 9.42 (s, 1H), 8.40 (d, 1H), 8.32 (s, 1H),8.11-8.09 (m, 2H), 7.48 (d, 1H), 7.38 (d, 1H), 7.20-7.18 (m, 1H), 5.97(s, 1H), 4.25-4.18 (m, 1H), 4.17 (s, 2H), 4.05 (d, 1H), 3.54 (s, 3H),3.42-3.38 (m, 3H), 2.86-2.78 (m, 2H), 2.23 (t, 2H), 2.09 (s, 3H); LCMS:85.3%, m/z = 576.90 (M+); HPLC: 93.5%, rt: 3.28 min. 0.059  1 70

¹H NMR (CDCl₃, 400 MHz): δ 9.23 (s, 1H), 8.37 (s, 2H), 8.01 (d, 1H),7.60-7.47 (m, 1H), 7.22-7.12 (m, 2H), 6.96 (d, 1H), 4.92-4.68 (m, 3H),4.29-4.25 (m, 2H), 3.10-2.96 (m, 2H), 2.77 (s, 3H), 2.53 (s, 3H),2.10-1.89 (m, 4H); LCMS: 99.78%, m/z = 530.35 (M + 1); HPLC: 95.11%, rt:3.18 min. 0.0043 1 71

¹H NMR (DMSO-d₆, 400 MHz): δ 9.18 (s, 1H), 8.53 (d, 1H), 8.31 (s, 1H),8.05 (d, 1H), 7.90-7.65 (m, 1H), 7.38-7.30 (m, 1H), 7.22 (dd, 2H),5.10-4.95 (m, 1H), 4.75-4.55 (m, 1H), 4.20-3.90 (m, 3H), 3.40-3.22 (m,2H), 2.98-2.80 (m, 2H), 2.78 (s, 3H), 2.50 (s, 3H), 2.30-2.00 (m, 2H);LCMS: 90.93%, m/z = 545.2 (M + 1); HPLC: 93.33%, rt: 3.29 min. 0.039  172

¹H NMR (CDCl₃, 400 MHz): δ 9.28 (s, 1H), 8.21 (d, 1H), 8.09-8.04 (t,2H), 7.39 (d, 1H), 7.26 (s, 1H), 7.20-7.18 (m, 1H), 5.97 (bs, 1H), 5.22(m, 1H), 4.98 (d, 2H), 4.22 (d, 2H), 3.82 (d, 2H), 3.53 (s, 3H), 3.25(t, 2H), 2.89 (s, 3H), 2.50-2.23 (m, 2H); LCMS: 99.3%, m/z = 577.2 (M +1); HPLC: 97.37%, rt: 3.27 min. 0.045  1 73

¹H NMR (CD₃OD, 400 MHz): δ 9.12 (s, 1H), 8.45-8.43 (d, 1H), 7.93-7.90(d, 1H), 7.62-7.60 (d, 1H), 7.49-7.40 (m, 2H), 7.15 (s, 1H), 7.03-7.01(d, 1H), 6.45-6.41 (t, 1H), 5.03-4.95 (m, 1H), 4.31-4.20 (m, 2H), 3.64(s, 3H), 3.11-2.99 (m, 2H), 2.81 (s, 3H), 2.72-2.61 (m, 2H), 2.05-1.95(m, 2H); LCMS: 99.72%, m/z = 560.95 (M+); HPLC: 95.59%, rt: 3.10 min.0.0036 1 74

¹H NMR (CDCl₃, 400 MHz): δ 9.29 (s, 1H), 8.44 (d, 1H), 8.06 (d, 2H),7.53 (d, 1H), 7.35 (s, 1H), 7.22 (d, 1H), 5.97 (bs, 1H), 4.88-4.55 (m,3H), 4.35-4.15 (m, 2H), 3.53 (s, 3H), 3.05 (bs, 2H), 2.80 (s, 3H),2.78-2.65 (m, 2H), 2.10-1.95 (m, 2H); LCMS: 90.8%, m/z = 562.2 (M + 1);HPLC; 97.04%, rt: 2.42 min. 0.01  5 75

¹H NMR (CDCl₃, 400 MHz): δ 9.39 (s, 1H), 8.69 (d, 1H), 8.36 (s, 1H),8.05 (d, 1H), 7.38-7.28 (m, 3H), 7.15-7.10 (m, 1H), 7.05-6.97 (m, 1H),6.28 (t, 1H), 4.89 (bs, 2H), 4.02-3.93 (m, 2H), 3.68 (s, 3H), 3.18-2.96(m, 4H), 2.07 (s, 3H), 1.96-1.87 (m, 2H); LCMS: 100%, m/z = 561.5 (M +1); HPLC: 98.16%, rt: 6.36 min. 0.0038 1 76

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.35 (s, 1H), 8.26 (bs, 1H),8.02 (d, 1H), 7.36 (s, 1H), 7.26 (s, 2H), 6.93 (d, 1H), 5.25-5.05 (m,1H), 4.78 (bs, 2H), 4.35-4.10 (m, 2H), 3.55-3.38 (m, 2H), 3.03 (t, 2H),2.79 (s, 3H), 2.55 (s, 3H), 2.25 (s, 3H), 2.01-1.89 (m, 2H); LCMS: 100%,m/z = 526.4 (M + 1); HPLC; 98.8%, rt: 3.71 min. 0.04  1 77

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.41 (d, 1H), 8.11 (bs, 1H),8.03 (d, 1H), 7.31 (s, 1H), 7.35-7.18 (m, 2H), 6.95 (d, 1H), 5.40-5.20(m, 1H), 5.02-4.90 (m, 1H), 4.25-4.10 (m, 1H), 3.90-3.78 (m, 2H),3.30-3.15 (m, 2H), 2.95-2.70 (m, 5H), 2.56 (s, 3H), 2.29 (s, 3H),2.01-1.89 (m, 2H); LCMS: 98.8%, m/z = 541.35 (M + 1); HPLC: 96.44%, rt:3.82 min. 0.08  1 78

¹H NMR (DMSO-d₆, 300 MHz): δ 9.16 (s, 1H), 8.50 (td, 1H), 8.45 (d, 1H),8.04 (d, 1H), 7.76-7.66 (m, 2H), 7.37 (d, 2H), 7.19 (d, 1H), 5.05-4.90(m, 1H), 4.70 (d, 1H), 4.55-4.45 (m, 1H), 4.20-4.10 (m, 2H), 4.00 (d,1H), 3.28-3.16 (m, 2H), 3.00-2.85 (m, 1H), 2.79 (s, 3H), 2.50 (s, 3H),2.30-2.05 (m, 3H); LCMS: 93.23%, m/z = 527.20 (M + 1); HPLC: 96.31%, rt:3.76 min. 0.179  1 79

¹H NMR (DMSO-d₆, 300 MHz): δ 9.37 (s, 1H), 8.75 (s, 1H), 8.63 (d, 1H),8.53 (d, 1H), 8.14 (d, 1H), 7.69 (t, 1H), 7.41 (dd, 1H), 7.25 (dd, 2H),5.93 (s, 2H), 3.70-3.55 (m, 2H), 3.38-3.20 (m, 2H), 2.69-2.58 (m, 2H),2.47 (s, 3H), 2.22-2.07 (m, 2H), 1.97 (s, 3H); LCMS: 100%, m/z = 530.7(M + 1); HPLC: 98.60%, rt: 3.99 min. 0.0092 1 80

¹H NMR (DMSO-d₆, 300 MHz): δ 9.35 (s, 1H), 8.73 (d, 3H), 8.62 (d, 1H),8.14 (d, 1H), 7.71 (t, 1H), 7.42 (dd, 1H), 7.36 (t, 1H), 7.28 (dd, 1H),5.95 (s, 2H), 3.70-3.55 (m, 2H), 2.65-2.50 (m, 4H), 2.25-2.08 (m, 2H),1.97 (s, 3H); LCMS: 93.81%, m/z = 516.2 (M + 1); HPLC: 99.37%, rt: 3.44min. 0.013  1 81

¹H NMR (CDCl₃, 300 MHz): δ 9.25 (s, 1H), 8.25-8.17 (m, 1H), 8.01 (d,1H), 7.44-7.31 (m, 2H), 7.15 (s, 1H), 7.01 (d, 1H), 6.24 (t, 1H),5.38-5.20 (m, 1H), 5.04-4.75 (m, 2H), 4.60-4.39 (m, 2H), 4.12-3.93 (m,1H), 3.80-3.78 (m, 1H), 3.65 (s, 3H), 3.43-3.17 (m, 1H), 2.95-2.75 (m,4H), 2.45-2.16 (m, 2H), 2.10-2.00 (m, 1H), 1.45-1.30 (m, 2H); LCMS:100%, m/z = 590.5 (M + 1); HPLC: 98.96%, rt: 6.43 min. 0.007  1 82

¹H NMR (DMSO-d₆, 400 MHz): δ 9.19 (s, 1H), 8.36 (m, 1H), 8.05 (d, 1H),7.66 (m, 1H), 7.55 (m, 1H), 7.47 (d, 1H), 7.37 (d, 1H), 6.78 (s, 1H),6.05-5.70 (m, 2H), 5.15-5.20 (m, 2H), 4.19 (d, 2H), 3.52 (s, 3H),2.92-2.89 (m, 2H), 2.77 (s, 3H), 2.33 (m, 1H), 2.11-2.19 (m, 2H); LCMS:96.41%, m/z = 562.1 (M + 1); HPLC: 97.48%, rt: 3.46 min. 0.0045 1 83

¹H NMR (DMSO-d₆, 300 MHz): δ 9.35 (s, 1H), 8.73 (s, 1H), 8.52 (t, 2H),8.13 (d, 1H), 7.73 (t, 1H), 7.40 (d, 1H), 7.24 (t, 2H), 4.48 (t, 1H),4.10 (d, 1H), 3.69 (d, 1H), 3.60-3.35 (m, 4H), 2.73-2.58 (m, 2H), 2.47(s, 3H), 2.35-2.20 (m, 2H), 1.97 (s, 3H); LCMS: 68.16%, m/z = 544.85(M + 1); HPLC: 98.85%, rt: 3.74 min. 0.047  1 84

1H NMR (DMSO-d₆, 400 MHz): δ 9.21 (s, 1H), 8.73 (d, 2H), 8.06 (d, 1H),7.73 (s, 1H), 7.64 (d, 1H), 7.43 (dd, 2H), 7.37 (t, 1H), 4.90 (s, 1H),3.70 (s, 2H), 3.02 (d, 3H), 2.77 (s, 3H), 2.50-2.40 (m, 2H), 2.11 (s,3H); LCMS: m/z = 96.73%, 528.1 (M + 1); HPLC: 96.48%, rt: 4.04 min.0.022  2 85

1H NMR (CDCl₃, 400 MHz): δ 9.33 (s, 1H), 8.70 (d, 1H), 8.63 (d, 2H),8.08 (d, 1H), 7.53 (dd, 1H), 7.46 (d, 1H), 7.29 (d, 1H), 7.16 (, 1H),5.70 (, 1H), 4.68 (q, 1H), 3.58-3.30 (m, 3H), 3.02 (s, 2H), 2.78 (s,3H), 2.78-2.65 (m, 2H), 2.21 (dt, 1H); LCMS: m/z = 91.66%, 546.1 (M +1); HPLC: 98.87%, rt: 4.65 min; 0.01% TFA in water, ACN:MeOH (1:1),Column: AG/C18/15-016. 0.011  2 86

¹HNMR (DMSO-d₆, 300 MHz): δ 9.22 (d, 1H), 8.73 (d, 1.7H), 8.61 (d,0.3H), 8.12-7.91 (m, 2H), 7.80-7.54 (m, 2H), 7.43 (dd, 1H), 7.37 (t,1H), 5.72-5.50 (m, 1H), 5.41-5.15 (m, 2H), 4.61-4.45 (m, 3H), 3.82-3.65(m, 1H), 3.13-2.95 (m, 2H), 2.85-2.80 (m, 2H), 2.76 (s, 3H), 2.37-2.21(m, 2H); LCMS: 100%, m/z = 591.0 (M+); HPLC: 98.85%, rt: 4.41 min.0.011  1 87

¹HNMR (CDCl₃, 300 MHz): δ 9.32 (s, 1H), 8.30 (s, 1H), 8.06 (d, 1H),7.95-7.86 (m, 1H), 7.58-7.35 (m, 2H), 7.30-7.26 (m, 1H), 5.71-5.08 (m,2H), 4.96-4.70 (m, 1H), 4.32-4.05 (m, 2H), 3.85-3.68 (m, 1H), 3.64-3.52(m, 1H), 3.35-3.13 (m, 1H), 3.00-2.87 (m, 2H), 2.79 (s, 3H), 2.56 (d,3H), 2.28-2.10 (m, 1H); LCMS: 98.34%, m/z = 597.1 (M + 1); HPLC: 98.81%,rt: 3.95 min. 0.0062 3 88

1HNMR (CDCl₃, 400 MHz): δ 9.31 (s, 1H), 8.65 (d, 2H), 8.03 (d, 2H),7.44-7.35 (m, 1H), 7.12 (t, 1H), 7.02-6.96 (m, 2H), 5.83-5.58 (m, 1H),5.20-4.67 (m, 2H), 4.32-4.01 (m, 2H), 3.85 (s, 3H), 3.78-3.67 (m, 1H),3.35-3.11 (m, 1H), 3.08-2.82 (m, 2H), 2.80 (s, 3H), 2.50-2.22 (m, 1H),2.21-1.98 (m, 1H); LCMS: 99.03%, m/z = 561.2 (M + 1); HPLC: 98.83%, rt:3.20 min. 0.0057 1 89

¹HNMR (CDCl₃, 400 MHz): δ 9.39 (s, 1H), 8.23 (d, 1H), 8.09 (d, 1H),8.01-7.82 (m, 1H), 7.52 (s, 1H), 7.51-7.36 (m, 1H), 7.31 (d, 1H), 7.12(d, 1H), 5.65-5.20 (m, 2H), 4.90-4.71 (m, 2H), 4.69 (d, 2H), 4.31-4.18(m, 1H), 4.17-4.09 (m, 1H), 3.85-3.75 (m, 1H), 3.35-3.18 (m, 1H),2.98-2.81 (m, 2H), 2.80 (s, 3H), 2.45-2.25 (m, 1H), 2.24-2.12 (m, 1H);LCMS: 98.12%, m/z = 595.1 (M + 1); HPLC: 95.34%, rt: 3.37 min. 0.0026 190

¹HNMR (CDCl₃, 300 MHz): δ 9.32 (s, 1H), 8.64 (d, 2H), 8.05 (d, 1H), 7.86(d, 1H), 7.25-7.16 (m, 3H), 7.11 (t, 1H), 5.62-5.21 (m, 2H), 4.96-4.68(m, 1H), 4.31-4.05 (m, 1H), 4.01-3.60 (m, 2H), 3.48-3.12 (m, 1H),3.05-2.86 (m, 1H), 2.86 (s, 3H), 2.36 (s, 3H), 2.32-2.10 (m, 2H); LCMS:99.20%, m/z = 545.2 (M + 1); HPLC: 98.15%, rt: 3.80 min. 0.0026 1 91

¹HNMR (DMSO-d₆, 600 MHz): δ 9.28 (d, 1H), 8.80-8.72 (m, 1.5H), 8.65 (d,0.5H), 8.12-7.98 (m, 1.5H), 7.92-7.80 (m, 0.5H), 7.23 (d, 0.5H), 7.67(d, 0.5H), 7.57-7.49 (m, 0.5H), 7.46-7.42 (m, 0.5H), 7.39-7.31 (m, 1H),7.28-7.23 (m, 0.5H), 7.20-7.12 (m, 0.5H), 5.68-5.56 (m, 1H), 5.54-5.46(m, 0.5H), 5.27-5.13 (m, 1H), 4.89-4.77 (m, 0.5H), 4.64-4.56 (m, 0.5H),4.50-4.40 (m, 2H), 4.37-4.22 (m, 0.5H), 4.17-4.03 (m, 1H), 3.10-2.93 (m,1H), 2.82 (s, 2H), 2.76 (s, 1H), 2.35-2.15 (m, 2H); LCMS: 100%, m/z =645.3 (M+); HPLC: 93.03%, rt: 3.36 min. 0.018  3 92

¹HNMR (CDCl₃, 300 MHz): δ 9.32 (s, 1H), 8.66 (d, 2H), 8.09 (dd, 2H),7.57 (t, 1H), 7.21-7.13 (m, 3H), 5.71-5.15 (m, 2H), 5.10-4.65 (m, 1H),4.42-4.05 (m, 2H), 4.01-3.63 (m, 1H), 3.55-3.10 (m, 1H), 3.08-2.90 (m,1H), 2.81 (s, 3H), 2.50-1.97 (m, 2H); LCMS: 92.79%, m/z = 549.2 (M + 1);HPLC: 96.64%, rt: 4.13 min. 0.032  1 93

¹H NMR (DMSO-d₆, 400 MHz): δ 9.23 (s, 1H), 8.71 (d, 2H), 8.30 (s, 1H),8.10-7.95 (m, 2H), 7.730-7.50 (m, 2H), 7.45-7.25 (m, 2H), 5.60-5.40 (m,1H), 5.22-5.07 (m, 1H), 4.60-4.38 (m, 1H), 2.81 (s, 3H), 2.74 (s, 3H),2.35-2.05 (m, 2H), 1.89-1.68 (m, 2H); LCMS: 97.71%, m/z = 549.3 (M + 1);HPLC: 96.77%, rt: 4.14 min. 0.025  1 94

¹H NMR (CDCl₃, 400 MHz): δ 9.33 (s, 1H), 8.60 (d, 2H), 8.10-8.02 (m,2H), 7.52 (d, 1H), 7.42 (s, 1H), 7.35-7.28 (m, 1H), 7.14 (t, 1H),5.70-5.40 (m, 1H), 5.00 (s, 2H), 4.82-4.45 (m, 2H), 4.40-3.95 (m, 1H),3.95-2.85 (m, 3H), 2.79 (s, 3H), 2.22-2.08 (m, 1H); LCMS: 97.71%, m/z =550.2 (M + 1); HPLC: 99.09%, rt: 3.49 min. 0.0027 1 95

¹H NMR (DMSO-d₆, 400 MHz): δ 9.29 (s, 1H), 8.70 (d, 2H), 8.01 (d, 2H),7.70-7.46 (m, 2H), 7.42-7.25 (m, 2H), 5.65-5.02 (m, 2H), 4.83-70 (m,1H), 4.62-4.25 (m, 2H), 3.28-3.05 (m, 2H), 2.78 (s, 3H), 2.67-2.64 (m,1H), 2.54-2.50 (m, 1H), 2.45-2.40 (m, 1H), 2.37-2.23 (m, 2H), 2.05-1.92(m, 1H); LCMS: 98.84%, m/z = 578.75 (M+); HPLC: 98.71%, rt: 4.15 min0.0073 1 96

¹H NMR (CDCl₃, 400 MHz): δ 9.27 (s, 1H), 8.63 (d, 2H), 8.27 (d, 1H),8.06 (d, 1H), 7.57-7.47 (m, 2H), 7.31 (dd, 1H), 7.13 (t, 1H), 5.38-5.21(m, 1H), 5.10-4.88 (m, 3H), 4.22-4.10 (m, 1H), 3.37-3.23 (m, 1H),2.92-2.83 (m, 2H), 2.81 (s, 3H), 2.48-2.21 (m, 3H); LCMS: 99.01%, m/z =549.1 (M + 1); HPLC: 95.02%, rt: 3.95 min. 0.04  1 97

¹H NMR (CDCl₃, 300 MHz): δ 9.31 (s, 1H), 8.62 (d, 2H), 8.32 (d, 1H),8.11-7.90 (m, 2H), 7.54-7.36 (m, 1H), 7.35-7.27 (m, 1H), 7.12 (t, 1H),5.60-5.32 (m, 1H), 5.30-5.07 (m, 1H), 4.99-4.65 (m, 2H), 4.63-4.37 (m,1H), 4.30-4.04 (m, 1H), 3.45-3.14 (m, 1H), 3.05-2.85 (m, 1H), 2.79 (s,3H), 2.44-2.32 (m, 1H), 2.26-2.13 (m, 1H); LCMS: 96.27%, m/z = 567.0(M + 1); HPLC: 98.21%, rt: 6.96 min. 0.011  1 98

¹HNMR (CDCl₃, 400 MHz): δ 9.29 (d, 1H), 8.63 (d, 2H), 8.30 (d, 0.5H),8.05 (d, 1H), 8.00 (d, 0.5H), 7.99 (d, 1H), 7.56 (d, 0.5H), 7.47 (d,1.5H), 7.29 (d, 1H), 7.13 (t, 1H), 5.61-5.15 (m, 2H), 5.13-4.85 (m, 1H),4.81-4.59 (m, 1H), 4.52-4.31 (m, 1H), 4.19-4.01 (m, 1H), 3.93 (brs, 1H),3.79-3.41 (m, 1H), 3.39-3.10 (m, 1H), 3.00-2.87 (m, 2H), 2.83 (s, 3H),2.68-2.48 (m, 2H); LCMS: 97.88%, m/z = 580.05 (M + 1); HPLC: 98.68%, rt:3.58 min. 0.04  1 99

¹HNMR (CDCl₃, 400 MHz): δ 9.32 (s, 1H), 8.73 (s, 1H), 8.09 (d, 1H), 7.92(brs, 1H), 7.55-7.45 (m, 2H), 7.31 (dd, 1H), 5.81-5.23 (m, 2H),5.10-4.72 (m, 1H), 4.28-4.10 (m, 1H), 4.09 (s, 3H), 3.90-3.75 (m, 1H),3.45 (brs, 1H), 3.39-3.15 (m, 1H), 3.10-2.91 (m, 1H), 2.82 (s, 3H),2.50-2.15 (m, 2H); LCMS: 100%, m/z = 596.2 (M + 1); HPLC: 97.88%, rt:3.83 min. 0.0085 1

Assays

Compounds of the invention were assessed for their ability to inhibitMEK activity. The inhibitory properties of the compounds of theinvention described herein can be evidenced by testing in any one of thefollowing assays.

[MEK1 1 mM ATP 1050 uM]

A BRAF-MEK-ERK cascade assay is used to evaluate the effects of thesecompounds as inhibitors of the MAP kinase pathway. An enzymatic cascadeassay is set up using recombinant human activated BRAF (V599E) kinase(Cat No. 14-557), human full length MEK1 kinase (Cat No. 14-706) andhuman full length active MAP Kinase 2/ERK2 (Cat No. 14-536) enzymesprocured from Upstate. TR-FRET (Time resolved fluorescence resonanceenergy transfer) detection technology is used for the read out. Theassay buffer solution contains 50 mM Tris pH 7.5, 10 mM MgCl2, 1 mM DTT,0.01% Tween 20, 0.1 nM activated BRAF, 2 nM inactive MEK1, 10 nMinactive ERK2, 1 mM ATP and 500 nM long chain biotin-peptide substrate(LCB-FFKNIVTPRTPPP) in a 384 well format. The kinase reaction is stoppedafter 90 minutes with 10 mM EDTA and Lance detection mix (2 nMEu-labeled phospho-serine/threonine antibody (Cat. No. AD0176-PerkinElmer), 20 nM SA-APC (Cat No. CR130-100-Perkin Elmer) is added. TheTR-FRET signal (Excitation at 340 nm, Emission at 615 nm and 665 nm) isread with 50 μs delay time on a Victor3 V fluorimeter. The data iscalculated using the ratio of readings at 665 nm to 615 nm. The finalconcentration of DMSO is 2.5% in the assay. Compounds are screened at 10μM concentration with pre-incubation of the enzymes in the presence oftest compound for 45 minutes.

Each individual IC₅₀ is determined using a 10 point dose response curvegenerated by GraphPad Prism software Version 4 (San Diego, Calif., USA)using non linear regression curve fit for sigmoidal dose response(variable slope). The IC₅₀ values obtained for the compounds of theinvention are listed in Table 1.2 above.

An in-vitro MAP kinase assay is set up using activated MAP kinase 2/ERK2(Cat. No. 14-550) obtained from Upstate. TR-FRET detection technology isused for the read out.

The assay buffer solution contains 50 mM Tris pH 7.5, 10 mM MgCl₂, 1 mMDTT, 0.01% Tween 20, 1 nM activated ERK2, 100 μM ATP and 500 nM longchain biotin-peptide substrate (LCB-FFKNIVTPRTPPP) in a 384 well format.The kinase reaction is stopped after 90 minutes with 10 mM EDTA andLance detection mix (2 nM Eu-labeled phospho-serine/threonine antibody(Cat. No. AD0176-Perkin Elmer), 20 nM SA-APC (Cat. No. CR130-100-PerkinElmer) is added. The TR-FRET signal (excitation at 340 nm, emission at615 nm and 665 nm) is read with 50 μs delay time on Victor3 Vfluorimeter. The data is calculated using the ratio of readings at 665nm to 615 nm. The final concentration of DMSO is 2.5% in the assay.Compounds are screened at 10 μM concentration with pre-incubation of theenzymes in the presence of test compound for 45 minutes. Compounds ofthe invention were found to be inactive in this assy, e.g. ex. 14 (16%inhibition at 10 uM), ex. 1A (55% inhibition at 10 uM).

The radioactive filter binding assay is standardized using recombinanthuman activated BRAF (V599E) kinase (Cat No. 14-557) and kinase deadMEK1 (K97R) (Cat No. 14-737) procured from Upstate. The incorporation of32P into MEK1 (K97R) by BRAF (V599E) is measured with final assay bufferconditions of 50 mM Tris pH 7.5, 10 mM MgCl2, 1 mM DTT, 100 mM sucrose,100 μM sodium orthovanadate, 5 μM ATP and 2 μCi [γ 32P] ATP and 500 mgMEK1 Kinase dead substrate. The enzymatic reaction is stopped after 120minutes with 8N HCl (hydrochloric acid) and 1 mM ATP. The solution isspotted on P81 filter paper and washed 4 times with 0.75%orthophosphoric acid and lastly with acetone. The dried P81 filterpapers are read in a Micro-beta Trilux scintillation counter. The finalconcentration of DMSO is 1% in the assay. Compounds are screened at 10μM concentration with pre-incubation of the enzymes in the presence oftest compound for 45 minutes. Compounds of the invention were found tobe inactive in this assy, e.g. ex. 33 (13% inhibition at 10 uM), ex. 1A(0% inhibition at 10 uM).

These assays described above are fully detailed in Han, Shulin, et. al.,Bioorganic & Medicinal Chemistry Letters (2005) 15, 5467-5473, and inYeh, et. al., Clin Cancer Res (2007) 13 (5), 1576-1583.

The cell viability assay in A375 cells (A375 ICW IC50 in Table 2) is setup in a 96-well plate format using XTT. XTT is a yellow tetrazolium saltthat is cleaved to an orange formazan dye by the mitochondria ofmetabolically active cells. The procedure allows for rapid determinationin a microtitre plate, to give reproducible and sensitive results.

A375 cells are grown in DMEM media containing 10% FBS and 1 mM sodiumpyruvate. Cells are trypsinized and seeded at 1000 cells/well. Afterallowing the cells to adhere overnight, compound is added to the wellsat the following final concentrations: 10, 3, 1, 0.3, 0.1, 0.03, 0.01,0.001, and 0.0001 μM. The assay is set up in triplicates for eachconcentration. DMSO concentrations are kept at 0.5%/well. Three daysafter compound addition, the XTT assay is performed. Wells are washedonce with PBS. 100 μL of DMEM media without phenol red or FBS is addedto each well. A working solution of XTT containing 1 mg/ml XTT and 100μL of PMS (stock concentration 0.383 mg/ml) per 5 ml is prepared. 50 μLof the working solution of XTT is added to each well. Absorbance of theplate is read at 465 nm using a Spectramax 190 (Molecular Devices). Theabsorbance from wells with media and XTT alone, but without cells isconsidered the blank and subtracted from readings from all wells. Thecell viability assay is further described in Scudiero, et. al., CancerResearch (1988) 48, 4827-4833; Weislow, et. al., J. Natl. CancerInstitute, (1989) 81, 577-586; and Roehm, et. al., J. Immunol. Methods[1991]142:257-265. The IC₅₀ values obtained for the compounds of theinvention are listed in Table 2 below.

TABLE 2 All IC₅₀ values are in uM. MEK1 1 mM A375 ICW A375 XTT ExampleATP IC50 IC50 IC50 uM  1A 0.005 0.0039 0.003  1B 0.138  2 0.726 3.272.41  3 0.104 0.652 0.368  4 0.309  5 0.04 0.28 0.321  6 0.062 0.2670.232  7 0.468  8 0.015 0.34 0.319  9 0.103 0.744 0.755 10 0.213 2.622.09 11 2.35 >10 6.55 12 0.212 0.712 0.414 13 0.515 1.88 1.11 14 0.00710.053 0.076 15 0.016 0.118 0.088 16 0.059 0.667 0.587 17 0.093 0.2240.132 18 0.013 0.247 0.14 19 0.333 1.7 0.643 20 0.157 0.669 0.683 210.028 0.071 0.085 22 1.346 >10 >10 23 0.322 24 0.021 0.22 0.161 25 0.6553.05 1.72 26 0.0043 0.004 0.011 27 0.073 0.365 0.362 28 0.0037 0.00470.0048 29 0.019 0.081 0.091 30 0.011 0.017 0.014 31 0.003 0.006 0.004732 0.032 0.1 0.094 33 0.028 0.06 0.054 34 0.088 0.151 0.212 35 0.0190.018 0.026 36 0.026 0.044 0.091 37 0.0027 0.009 0.008 38 0.0046 0.0630.119 39 0.455 40 0.186 41 0.022 0.62 2.8 42 0.085 0.239 0.208 43A 0.060.848 0.677 43B 0.547 3.8 2.38 44 0.002 0.026 0.011 45 0.191 >10 4.27 460.01 0.206 2.63 47 0.0017 0.016 0.011 48 0.011 0.044 0.025 49 0.2320.019 0.034 50 0.012 0.072 0.067 51 0.001 0.021 0.004 52 0.009 0.1090.159 53 0.0062 0.029 0.012 54 0.0015 0.042 0.025 55 0.047 0.231 0.31956 0.28 57 0.019 0.089 0.041 58 0.003 0.014 0.008 59 0.018 0.609 1.6 600.113 0.499 1.71 61 0.211 0.168 0.193 62 0.0037 0.049 0.055 63 0.00850.245 0.714 64 0.0053 0.007 0.016 65 0.0024 0.005 0.004 66 0.01 67 0.0530.539 0.281 68 0.0047 0.007 0.0025 69 0.059 0.272 0.708 70 0.0043 0.0330.06 71 0.039 0.076 0.144 72 0.045 0.197 0.623 73 0.0036 0.175 0.254 740.01 1.55 3.64 75 0.0038 0.259 0.194 76 0.04 0.022 0.013 77 0.08 0.0650.09 78 0.179 79 0.0092 0.007 0.0056 80 0.013 0.06 0.08 81 0.007 0.3811.148 82 0.0045 2.18 2.33 83 0.047 0.088 0.301 84 0.022 0.058 0.225 850.011 0.016 0.021 86 0.011 0.176 0.175 87 0.0062 0.029 0.012 88 0.00570.053 0.108 89 0.0026 0.04 0.045 90 0.0026 0.019 0.02 91 0.018 >10 >1092 0.032 0.145 0.135 93 0.025 0.064 0.061 94 0.0027 0.006 0.005 950.0073 0.027 0.031 96 0.04 0.359 0.394 97 0.011 0.112 0.09 98 0.04 0.5470.557 99 0.0085 0.035 0.531

Percentage viability is calculated considering the blank subtractedvalue from wells treated with DMSO alone as 100% viable. IC₅₀ values arecalculated using Graphpad Prism, using non-linear regression curve fitfor sigmoidal dose response (variable slope). Compounds of the inventionwere evaluated in this cell viability assay. The IC₅₀ values obtainedfor the compounds of the invention are listed in Table 2 above.

A375 P-Erk (In-Cell-Western) (A375 ICW IC50 in Table 2):

Human melanoma A375 cells were seeded at 50,000 cells per well in 100 μlgrowth medium in Costar 96 well black clear bottom plates and placed at37° C./5% CO₂ over night. Test compounds were diluted in DMSO togenerate a concentration curve. A 5 mM stock was used for the highestconcentration at 500 times; to yield a final concentration of 10 μM with3-fold dilutions down to 0.0001 μM. 1 μl of diluted compound was addedto 500 μl cell culture media and mixed well. Media was removed fromcells and 200 μl of media containing compound was added. Cells weretreated for 3 hrs with compound at 37° C., 5% CO₂.

After the compound incubation, cells were washed once with PBS (Mg andfixed in 4% paraformaldehyde/PBS for 1 hr at room temperature. Followingfixation, cells were washed three times with PBS/0.1% TritonX-100(PBST),and then blocked with 5% skimmed milk/PBST, for 1-2 hr. 50 μL per wellprimary antibody was added (rabbit-anti-phospho-ERK1/2) at 1:500 in 5%skimmed milk/PBST and incubated overnight at 4° C. Cells were washedfour times with 100 μl DELFIA wash buffer and 50 μL per well secondaryantibody was added (DELFIA-EU-N-1-labeled anti-rabbit antibody) at1:3000 in DELFIA assay buffer and incubated for 2 hr at room temperaturein the dark (covered). Cells were washed 4× with 100 ml DELFIA washbuffer. 50 μL per well Wallac-DELFIA enhancement solution was added.Plates were shaken at room temperature for 20 min and then read on thePerkin Elmer Victor3v reader on the Europium setting(emission/excitation of 615/340 nm).

IC₅₀ values were calculated using DMSO diluent values as 0% inhibitionand counts of the highest tested concentration of the referenceinhibitor as 100% inhibition. All the concentrations along with DMSOwere done in triplicates. The IC_(50 values)s obtained for the compoundsof the invention are listed in table 2.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims.

We claim:
 1. A compound of formula I:

wherein n is selected from 0, 1, 2 and 3; R₁ is selected from:

R₂ is selected from chloro, methyl, hydrogen, fluoro and methoxy; R_(3a)is selected from cyano-methyl, 2-hydroxy-ethyl, 1-hydroxypropan-2-yl,3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-methoxy-ethyl,2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl, methyl-sulfonyl,amino-carbonyl-methyl, cyclopropyl-sulfonyl, isopropyl-sulfonyl,dimethylcarbamoyl, 3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl,2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl,(2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, oxetan-3-ylmethyl,(S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl,carbamoyl, (oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl,2-fluoroethanoyl, 3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl; eachR₄ is independently selected from hydrogen, halo, methyl andhydroxy-methyl; and optionally two R₄ groups together with the carbonatoms to which they are attached form —(CH₂)₂₋₃—; R₅ is selected fromhydrogen and methyl; R₆ is selected from hydrogen, methoxy and halo; R₇is selected from hydrogen, fluoro, CF₃, CH₂OH, cyclopropyl and methyl;and R₈ is cyano; or the pharmaceutically acceptable salts thereof. 2.The compound of claim 1, wherein: n is selected from 0 or 1; R₁ isselected from:

R₂ is selected from chloro, methyl, hydrogen, fluoro and methoxy; R_(3a)is selected from cyano-methyl, 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl,methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl,2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl,oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl,2-amino-2-oxoethyl, carbamoyl, (oxetan-2-yl)-methanoyl,2-(sulfooxy)acetyl, 2-fluoroethanoyl, 3-hydroxypropanoyl, andN,N-dimethylsulfonamidyl; each R₄ is independently selected from halo,methyl and hydroxy-methyl; R₅ is selected from hydrogen and methyl; R₆is selected from hydrogen and halo; and R₇ is selected from hydrogen,fluoro, CF₃, CH₂OH, cyclopropyl and methyl; or the pharmaceuticallyacceptable salts thereof.
 3. The compound of claim 1, wherein: n isselected from 0 or 1; R₁ is selected from:

R₂ is selected from chloro, methyl, hydrogen, fluoro and methoxy; R_(3a)is selected from 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-fluoropropanoyl, methyl-sulfonyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl,2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl,(S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, carbamoyl,2-(sulfooxy)acetyl, 2-fluoroethanoyl, 3-hydroxypropanoyl, andN,N-dimethylsulfonamidyl; each R₄ is independently selected from halo,methyl and hydroxy-methyl; R₅ is selected from hydrogen and methyl; R₆is selected from hydrogen and halo; and R₇ is selected from hydrogen,fluoro, CF₃, CH₂OH, cyclopropyl and methyl; or the pharmaceuticallyacceptable salts thereof.
 4. The compound of claim 1, wherein: n isselected from 0 or 1; R₁ is selected from:

R₂ is selected from chloro and methoxy; R_(3a) is selected from3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-fluoropropanoyl,dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl,(2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, (S)-2-hydroxypropanoyl,2-hydroxypropanoyl, acetyl, carbamoyl, 2-(sulfooxy)acetyl,2-fluoroethanoyl and 3-hydroxypropanoyl; each R₄ is independentlyselected from halo, methyl and hydroxy-methyl; R₅ is selected fromhydrogen and methyl; R₆ is hydrogen; and R₇ is hydrogen; or thepharmaceutically acceptable salts thereof.
 5. The compound of claim 1 offormula Ie:

wherein: R₁ is selected from:

R₂ is selected from chloro, methyl, fluoro and methoxy; R_(3a) isselected from cyano-methyl, 2-hydroxy-ethyl, 1-hydroxypropan-2-yl,3-hydroxy-2-(hydroxy-methyl)propanoyl, 2-methoxy-ethyl,2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl, methyl-sulfonyl,amino-carbonyl-methyl, cyclopropyl-sulfonyl, isopropyl-sulfonyl,dimethylcarbamoyl, 3-hydroxy-2-(hydroxy-methyl)propyl, 2-hydroxy-propyl,2-hydroxyacetyl, 2-acetoxyacetyl, 2-methoxyacetyl,(2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl, oxetan-3-ylmethyl,(S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, 2-amino-2-oxoethyl,carbamoyl, (oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl,2-fluoroethanoyl, 3-hydroxypropanoyl, and N,N-dimethylsulfonamidyl;R_(4a) is selected from hydrogen and methyl; R_(4b) is selected fromhydrogen and fluorine; R₅ is selected from hydrogen and methyl; R₆ isselected from hydrogen and fluoro; R₇ is selected from hydrogen, fluoro,CF₃, CH₂OH, cyclopropyl and methyl; and R₈ is cyano; or thepharmaceutically acceptable salts thereof.
 6. The compound of claim 1 offormula Ie:

wherein R₁ is selected from:

R₂ is selected from chloro, methyl, fluoro and methoxy; R_(3a) isselected from cyano-methyl, 3-hydroxy-2-(hydroxy-methyl)propanoyl,2-methoxy-ethyl, 2-fluoropropanoyl, (3-methyloxetan-3-yl)-methyl,methyl-sulfonyl, amino-carbonyl-methyl, cyclopropyl-sulfonyl,isopropyl-sulfonyl, dimethylcarbamoyl, 2-hydroxyacetyl, 2-acetoxyacetyl,2-methoxyacetyl, (2,2,2-trifluoroethyl)carbamoyl, 2-aminoacetyl,oxetan-3-ylmethyl, (S)-2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl,2-amino-2-oxoethyl, carbamoyl, (oxetan-2-yl)-methanoyl,2-(sulfooxy)acetyl, 2-fluoroethanoyl, 3-hydroxypropanoyl, andN,N-dimethylsulfonamidyl; R_(4a) is hydrogen; R_(4b) is fluorine; R₅ ismethyl; R₆ is hydrogen and fluoro; and R₇ is selected from hydrogen,CF₃, CH₂OH, and methyl; or the pharmaceutically acceptable saltsthereof.
 7. The compound of claim 1 of formula Ie:

wherein R₁ is selected from:

R₂ is selected from chloro, methyl, fluoro and methoxy; R_(3a) isselected from cyano-methyl, methyl-sulfonyl, 2-hydroxyacetyl,2-acetoxyacetyl, 2-methoxyacetyl, (S)-2-hydroxypropanoyl, acetyl,carbamoyl, (oxetan-2-yl)-methanoyl, 2-(sulfooxy)acetyl, 2-fluoroethanoyland 3-hydroxypropanoyl; R_(4a) is hydrogen; R_(4b) is fluorine; R₅ ismethyl; R₆ is selected from hydrogen and fluoro; and R₇ is selected fromhydrogen, CF₃, CH₂OH, and methyl; or the pharmaceutically acceptablesalts thereof.
 8. The compound of claim 1 selected from:1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone;1-((3R,4R)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone;8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-(1-(2-methoxyethyl)piperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinolone;2-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)ethanol;8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1-(1-((3-methyloxetan-3-yl)methyl)piperidin-4-yl)-1H-imidazo[4,5-c]quinolone;8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]quinolone;1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one;1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)propan-2-ol;8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-1-(1-(cyclopropylsulfonyl)piperidin-4-yl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolone;8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-(1-(isopropylsulfonyl)piperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinolone;4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-N,N-dimethylpiperidine-1-sulfonamide;4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-N,N-dimethylpiperidine-1-carboxamide;1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)ethanone;2-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)acetamide;1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone;2-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)ethanol;2-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)propan-1-ol;2-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)ethanol;2-(4-(7-fluoro-8-(2-methoxy-4-((4-methylpyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)ethanol;2-(4-(7-fluoro-8-(2-methoxy-4-(pyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)ethanol;1-(4-(7-fluoro-8-(2-methoxy-4-((4-methylpyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxypropan-1-one;1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxypropan-1-one;1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-3-hydroxy-2-(hydroxymethyl)propan-1-one;2-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)methyl)propane-1,3-diol;1-(4-(7-fluoro-8-(2-methoxy-4-((4-methylpyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxyethanone;8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1-(1-(oxetan-3-ylmethyl)piperidin-4-yl)-1H-imidazo[4,5-c]quinolone;1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxyethanone;1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxypropan-1-one;1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone;1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one;4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide;4-(8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide;8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1-(1-(methylsulfonyl)piperidin-4-yl)-1H-imidazo[4,5-c]quinolone;1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxyethanone;(S)-1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one;(S)-1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one;2-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)ethanol;4-(7-fluoro-8-(2-methoxy-4-((4-methylpyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidine-1-carboxamide;4-(7-fluoro-8-(2-methoxy-4-(pyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidine-1-carboxamide;2-amino-1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)ethanone;2-amino-1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)ethanone;1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-4-(hydroxymethyl)piperidin-1-yl)-2-hydroxyethanone;1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-methoxyethanone;(R orS)-1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-fluoropropan-1-one(Peak 1); (R orS)-1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-fluoropropan-1-one(Peak 2);1-(4-(8-(2-chloro-4-((6-(hydroxymethyl)pyridin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone;4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-(2,2,2-trifluoroethyl)piperidine-1-carboxamide;1-(4-(8-(2-chloro-4-((4-fluoropyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone;1-(4-(8-(2-chloro-4-((6-fluoropyridin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone;1-(4-(8-(2-chloro-4-((5-fluoro-4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone;2-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-oxoethylacetate;8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-((3S,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinolone;1-((3S,4S)-4-(8-(2-chloro-4-(4-(trifluoromethyl)pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone;1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-methoxyethanone;1-((3S,4S)-4-(8-(2-chloro-4-((5-fluoro-4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone;1-(4-(8-(2-chloro-4-((4-cyclopropylpyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone;4-(8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)tetrahydro-2H-thiopyran1,1-dioxide;8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1-(3-fluorotetrahydro-2H-pyran-4-yl)-2-methyl-1H-imidazo[4,5-c]quinolone;2-((3R,4R)-4-(8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)acetonitrile;2-((3S,4S)-4-(8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)acetonitrile;4-(3-chloro-4-(1-(1-(cyanomethyl)piperidin-4-yl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)phenoxy)-6-methylpyrimidine-2-carbonitrile;2-(4-(8-(2-chloro-4-((1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)acetonitrile;2-((3R,4R)-3-fluoro-4-(7-fluoro-8-(2-methoxy-4-(pyrimidin-2-yloxy)phenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)acetonitrile;2-((3S,4S)-3-fluoro-4-(7-fluoro-8-(2-methoxy-4-(pyrimidin-2-yloxy)phenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)acetonitrile;3-(3-chloro-4-(7-fluoro-1-(1-(2-hydroxyacetyl)piperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)phenoxy)-1-methylpyridin-2(1H)-one;4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidine-1-carboxamide;4-(8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidine-1-carboxamide;1-(4-(8-(2-chloro-4-((4-methoxy-6-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxyethanone;1-(4-(8-(2-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-methoxyethanone;1-((3S,4S)-4-(8-(2-chloro-4-((4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone;6-(3-chloro-4-(7-fluoro-1-(1-(2-hydroxyacetyl)-4-methylpiperidin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)phenoxy)-3-methylpyrimidin-4(3H)-one;4-(7-fluoro-8-(2-fluoro-4-((4-methylpyrimidin-2-yloxy)phenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide;1-(4-(7-fluoro-8-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone;6-(3-chloro-4-(7-fluoro-1-(1-(2-hydroxyacetyl)piperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)phenoxy)-3-methylpyrimidin-4(3H)-one;4-(8-(2-chloro-4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide;4-(8-(2-chloro-4-((1-methyl-6-oxo-1,6-dihydropyrimidin-4-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide;4-(8-(2-chloro-4-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)phenyl)-7-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidine-1-carboxamide;4-(7-fluoro-2-methyl-8-(2-methyl-4-((4-methylpyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide;1-(4-(7-fluoro-2-methyl-8-(2-methyl-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone;1-(4-(7-fluoro-2-methyl-8-(4-((4-methylpyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone;4-(7-fluoro-8-(2-fluoro-4-((4-methylpyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidine-1-carboxamide;4-(7-fluoro-8-(2-fluoro-4-(pyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidine-1-carboxamide;(S)-3-(3-chloro-4-(7-fluoro-1-(1-(2-hydroxypropanoyl)piperidin-4-yl)-2-methyl-1H-imidazo[4,5-c]quinolin-8-yl)phenoxy)-1-methylpyridin-2(1H)-one;4-(8-(2-chloro-4-((4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)oxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidine-1-carboxamide;1-(4-(7-fluoro-8-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)-4-methylpiperidin-1-yl)-2-hydroxyethanone;2-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)acetonitrile;2-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)acetonitrile;((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)(oxetan-2-yl)methanone;1-((3S,4S)-4-(8-(2-chloro-4-((5-fluoro-4-methylpyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone;1-((3S,4S)-3-fluoro-4-(7-fluoro-8-(2-methoxy-4-(pyrimidin-2-yloxy)phenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone;1-((3S,4S)-4-(8-(2-chloro-4-((4-(hydroxymethyl)pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone;1-((3S,4S)-3-fluoro-4-(7-fluoro-2-methyl-8-(2-methyl-4-(pyrimidin-2-yloxy)phenyl)-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone;2-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-oxoethylhydrogen sulfate;1-((3S,4S)-3-fluoro-4-(7-fluoro-8-(2-fluoro-4-(pyrimidin-2-yloxy)phenyl)-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-hydroxyethanone;1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)ethanone;4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidine-1-carboxamide;(S)-1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxypropan-1-one;1-(4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)piperidin-1-yl)-2-fluoroethanone;1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-fluoroethanone;1-((3S,4S)-4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-3-hydroxypropan-1-one;and1-((3S,4S)-4-(8-(2-chloro-4-((4-methoxy-1,3,5-triazin-2-yloxy)phenyl)-7-fluoro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-3-fluoropiperidin-1-yl)-2-hydroxyethanone.9. A pharmaceutical composition comprising a compound according to claim8, or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 10. A combination comprising acompound according to claim 8, or a pharmaceutically acceptable saltthereof, and one or more therapeutically active agents.
 11. Apharmaceutical composition according to claim 9 for use in the treatmentof a disorder or disease which is mediated by the activity of MEK, forexample a disease or disorder selected from ovarian carcinoma, kidneycancer, prostate cancer, breast carcinoma, lymphomas, myeloma, bladdercarcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma,endometrial cancer, lung cancer, pancreatic cancer, gastric cancer andsoft tissue sarcomas selected from rhabdomyosarcoma, synovial sarcomaand Ewing sarcoma; in particular melanoma, pancreatic, colon, lung,kidney and ovarian cancers.
 12. A method of treatment an MEK-mediateddisorder selected from ovarian carcinoma, kidney cancer, prostatecancer, breast carcinoma, lymphomas, myeloma, bladder carcinoma, coloncancer, cutaneous melanoma, hepatocellular carcinoma, endometrialcancer, lung cancer, pancreatic cancer, gastric cancer and soft tissuesarcomas selected from rhabdomyosarcoma, synovial sarcoma and Ewingsarcoma, comprising the step of administering to a patient in needthereof a therapeutically effective amount of a compound of claim 8, ora pharmaceutically acceptable salt thereof.
 13. The method of claim 12wherein the MEK-mediated disorder is a cancer selected from melanoma,pancreatic, colon, lung, kidney and ovarian cancers.